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The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease

Cite this: J. Med. Chem. 2020, 63, 10, 5031–5073
Publication Date (Web):January 13, 2020
https://doi.org/10.1021/acs.jmedchem.9b01701
Copyright © 2020 American Chemical Society
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Abstract

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type 2 diabetes mellitus, and dyslipidemia has led to an emerging picture of NASH as the liver manifestation of metabolic syndrome. Although diet and exercise can dramatically improve NASH outcomes, significant lifestyle changes can be challenging to sustain. Pharmaceutical therapies could be an important addition to care, but currently none are approved for NASH. Here, we review the most promising targets for NASH treatment, along with the most advanced therapeutics in development. These include targets involved in metabolism (e.g., sugar, lipid, and cholesterol metabolism), inflammation, and fibrosis. Ultimately, combination therapies addressing multiple aspects of NASH pathogenesis are expected to provide benefit for patients.

Introduction

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Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition defined by the presence of ≥5% liver steatosis in the absence of significant alcohol consumption, steatogenic medication, or monogenic hereditary disorders.(1) NAFLD is subdivided into nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) based on histological examination of liver biopsy for the presence of inflammation or hepatocellular damage known as ballooning.(1) Whereas NAFL is usually considered benign, NASH can progress to serious liver damage, including cirrhosis, liver failure, and hepatocellular carcinoma (HCC).(2,3) Currently, there are no approved pharmaceutical therapies for the treatment of NASH.
The global prevalence of NAFLD is estimated to be 25%.(4) The exact prevalence of NASH is difficult to determine since its definitive diagnosis requires a liver biopsy (Box 1),(5−7) but estimates suggest the disease affects between 1.5% and 6.45% of the world population.(4) NAFLD prevalence varies with gender, race, and geographical location.(4) These differences may be explained by diet, environmental factors, or certain genetic polymorphisms.(8) In general, NAFLD patients have increased mortality compared with control populations, with cardiovascular disease as one of the most common causes of death. Furthermore, NAFLD patients diagnosed with HCC have poorer outcomes than HCC patients without NAFLD.(9) NAFLD/NASH will soon surpass hepatitis C virus infection as the leading indicator for liver transplantation.(2)
Box 1

Diagnostics for NASH

Liver biopsy is the gold standard and is widely used in the clinic, although it has limitations of cost, scalability, sample error, and safety. Liver biopsy results are described by the following scores:
  • NAFLD activity score (NAS) of 0 (healthy) to 8 (severe disease) is an unweighted sum of histological assessments of steatosis, lobular inflammation, and ballooning.

  • SAF score (steatosis, activity, and fibrosis) measures steatosis, inflammation, ballooning, and fibrosis.

  • Liver fibrosis staging (F0–F4) is widely used to evaluate the extent and location of fibrosis. The most severe stage of fibrosis (F4) is called cirrhosis.

Noninvasive markers are in development to overcome the limitations of liver biopsy and are being deployed in early phase clinical trials. These include blood markers and imaging techniques:
  • Blood markers of steatosis and inflammation: triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), and C-X-C motif chemokine 10 (CXCL10 or IP10).

  • Blood markers of apoptosis and fibrosis: cytokeratin 18 (CK18) and N-terminal type III collagen pro-peptide (pro-C3).

  • Magnetic resonance imaging protein density fat fraction (MRI-PDFF) to assess liver steatosis.

  • Magnetic resonance elastography (MRE) to evaluate liver stiffness and fibrosis.

  • Multiparametric MRI-based techniques that can accurately quantify steatosis as well as fibrosis and inflammation (iron-corrected T1 [cT1]).

It has long been appreciated that metabolic syndrome, including obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia, are risk factors for NAFLD, leading to the concept of NAFLD as the liver manifestation of metabolic syndrome.(10) Obesity and T2DM are the most commonly associated risk factors, with NAFLD presenting in the majority of patients undergoing bariatric surgery for weight loss(11) and in more than two-thirds of T2DM patients.(12) Although still not completely understood, a mechanistic picture of NASH disease progression is emerging. It is generally thought that overaccumulation of liver fat (steatosis) in NAFL patients leads to the production of cytotoxic lipid oxidation side-products and the establishment of the chronic necro-inflammatory state that defines NASH. Importantly, NAFL patients do not necessarily transition to NASH on the basis on steatosis alone. Rather, a myriad of conspiring factors, including metabolic dysfunction, insulin resistance, and glucose dysregulation contribute to the disease state. Ultimately, the necro-inflammatory environment of the NASH liver triggers pathological activation of hepatic stellate cells and the development of liver fibrosis. Fibrosis is the result of excess connective tissue (i.e., collagen) deposition in response to injury or inflammatory stimuli. In the liver, severe fibrosis can lead to scarring, cirrhosis, and eventually liver failure. Notably, fibrosis is the only histological marker that is significantly associated with mortality and liver failure in NASH patients.(13)
Strategies to treat NASH echo those used for T2DM and obesity, often emphasizing lifestyle changes, including exercise, diet, and weight loss. In one study, NASH patients who were able to achieve >10% weight loss showed improvement in all parameters of NASH, including inflammation and fibrosis.(14) In another study, 85% of obese patients with biopsy-confirmed NASH achieved resolution of the disease and showed improved fibrosis scores at 1 year after bariatric surgery.(15) These data provide compelling evidence that lifestyle changes, and weight loss in particular, can have therapeutic benefit in NASH patients. However, sustained meaningful weight loss can be very challenging to achieve. Safe, effective pharmacological interventions are therefore needed to bridge this gap and provide immediate benefit to patients.
Pharmaceutical therapeutic strategies for NASH have emerged with the goal of disrupting one or more steps involved in disease progression. Promising therapies are in development to improve metabolic function, reduce steatosis, decrease inflammation, and halt or reverse the progression of fibrosis (Figure 1). Not surprisingly, many drugs being actively pursued for NASH are medicines that are already approved or in development to treat T2DM and obesity. Ultimately, combination therapies are expected to be the most useful in this disease, by attacking multiple interconnected pathways to slow or reverse disease progression. Here, we review some of the most promising targets for NASH, as well as describe compounds being developed against these targets in the clinic (Table 1 and Table 2).

Figure 1

Figure 1. NASH disease is a complex metabolic syndrome that manifests in the liver. Drug targets that are under investigation for NASH and discussed in this review are shown, along with their primary mode(s) of action. It should be noted that some targets are involved in multiple aspects of NASH.

Table 1. NASH Targets and Clinical Stage Therapeutics
targetdrug namestudy phaseindication(s)clinical trial IDstudy completion
Metabolic Targets
ACC37 (firsocostat)Ph 2NASHNCT02856555July 2017
PF-05221304Ph 2NASHNCT03248882Mar 2019
Ph 1healthyNCT02871037Mar 2017
34 (MK-4074)Ph 1NAFLDNCT01431521Oct 2012
      
AMPKPXL770Ph 2NAFLDNCT03763877Feb 2020
Ph 1healthyNCT03395470Mar 2018
      
DGATIONIS-DGAT2RxPh 2T2DM/NAFLDNCT03334214Nov 2018
39 (AZD7687)Ph 1obesityNCT01119352Mar 2011
LY3202328Ph 1obesity/dyslipidemiaNCT02714569Feb 2017
PF-06865571Ph 1NASHNCT03513588Apr 2019
      
FASN42 (ASC40)Ph 2NASHNCT03938246May 2020
FT-4101Ph 1/2NASH/obesityNCT04004325Mar 2020
      
FGF19NGM282Ph 2NASHNCT03912532Dec 2020
Ph 2NASHNCT02443116Sept 2019
      
FGF21BMS-986036Ph 2NASHNCT03486899Sep 2021
Ph 2NASHNCT03486912Apr 2021
Ph 2NASHNCT02413372Jun 2017
BIO89-100Ph 1/2NASHNCT04048135Jun 2020
AKR-001Ph 2NASHNCT03976401Jun 2020
      
FXR7 (OCA)Ph 3NASHNCT02548351Oct 2022
12 (cilofexor)Ph 2NASHNCT02854605Jan 2018
Ph 1NASHNCT02654002Jul 2016
13 (tropifexor)Ph 2NASHNCT02855164Apr 2020
14 (nidufexor)Ph 2NASHNCT02913105Sep 2018
EDP-305Ph 2NASHNCT03421431Jul 2019
Ph 1NASHNCT03207425Sep 2017
15 (EYP001a)Ph 2NASHNCT03812029Jan 2020
Ph 1healthy/NASHNCT03976687Oct 2019
11 (Px-102)Ph 1healthyNCT01998659Dec 2011
Ph 1healthyNCT01998672Oct 2012
MET409Ph 2NASHNA 
10 (TERN-101)Ph 1healthyNA 
      
GLP-1R53 (liraglutide)Ph 3NASHNCT02654665Dec 2018
Ph 4T2DM/NAFLDNCT03068065Oct 2015
Ph 2T2DM/NASHNCT01399645Jun 2014
Ph 2NASHNCT01237119Jul 2014
52 (exenatide)Ph 2/3NAFLDNCT00650546Aug 2010
54 (semaglutide)Ph 2NASHNCT03884075Jan 2023
Ph 2NASHNCT02970942Apr 2020
TTP273Ph 2T2DMNCT02653599Jan 2017
OWL833Ph 1T2DMNA 
58 (PF-06882961)Ph 2T2DMNCT03985293Feb 2021
Ph 1T2DMNCT03538743Jun 2019
Ph 1healthyNCT03492697Jul 2018
Ph 1healthyNCT03309241Mar 2018
      
IBAT47 (elobixibat)Ph 2NASHNCT04006145May 2020
46 (volixibat)Ph 2NASHNCT02787304Jul 2018
Ph 1NASHNCT02287779Jun 2015
      
KHKPF-06835919Ph 2T2DM/NAFLDNCT03969719Feb 2021
Ph 2NAFLDNCT03256526Apr 2018
      
MPC43 (MSDC-0602K)Ph 3NASHNCT03970031Dec 2021
Ph 2NASHNCT02784444Jun 2019
      
PPAR3 (pioglitazone)Ph 3NASHNCT00063622Sep 2009
4 (elafibranor)Ph 3NASHNCT02704403Dec 2021
Ph 2NASHNCT01694849Dec 2015
5 (seladelpar)Ph 2NASHNCT03551522Dec 2020
      
SCD168 (aramchol)Ph 3NASHNCT04104321Dec 2024
Ph 2/3NASHNCT02279524May 2018
Ph 2NASHNCT01094158Jan 2012
      
SGLT263 (canagliflozin)Ph 4T2DM/NASHUMIN000023044Nov 2018
Ph 4T2DM/NAFLDUMIN000018166Jun 2017
65 (empagliflozin)Ph 4T2DM/NAFLDNCT02964715Nov 2018
NANAFLDNCT02686476Dec 2017
64 (ipragliflozin)Ph 4T2DM/NAFLDNCT02875821Jun 2017
61 (dapagliflozin)Ph 3NASHNCT03723252Nov 2021
Ph 4NAFLDUMIN000022155Sep 2018
Ph 4T2DM/NAFLDUMIN000023574Jul 2016
67 (luseogliflozin)Ph 4T2DM/NAFLDUMIN000016090Jun 2017
Ph 4T2DM/NAFLDUMIN000021087May 2017
      
THR-β20 (MGL-3196)Ph 3NASHNCT03900429Jun 2021
Ph 2NASHNCT02912260Apr 2018
Ph 1healthyNCT01519531Nov 2012
23 (VK2809)Ph 2NAFLDNCT02927184Mar 2019
Inflammation Targets
ASK172 (selonsertib)Ph 3NASHNCT03053050Jun 2019
Ph 3NASHNCT03053063Apr 2019
Ph 2NASHNCT02466516Oct 2016
      
Caspase74 (emricasan)Ph 2NASHNCT02686762Feb 2019
Ph 2cirrhosisNCT03205345Aug 2019
      
CCR2/576 (cenicriviroc)Ph 3NASHNCT03028740Oct 2021
Ph 2NASHNCT02217475Jun 2017
      
MR78 (MT-3995)Ph 2NASHNCT02923154Apr 2019
      
VAP-182 (BI-1467335)Ph 2NAFLDNCT03166735Jun 2019
TERN-201Ph 1healthyNA 
Fibrosis Targets
Gal-3GR-MD-02Ph 2NASH/cirrhosisNCT02462967Oct 2017
      
LOXL2simtuzumabPh 2PSCNCT01672853Aug 2016
Ph 2NASHNCT01672879Jan 2017
Ph 2NASHNCT01672866Dec 2016
84 (PAT-1251)Ph 1healthyNCT02852551Nov 2016
PXS-5153APh 1healthyNA 
Table 2. Phase 2 Combination Clinical Trials for the Treatment of NASH
target(s)drug name(s)target combination(s)clinical trial IDstudy completion
ACC37 (firsocostat)ASK1 + ACC; ASK1 + FXR; ACC + FXRNCT03449446Oct 2019
ASK172 (selonsertib)
FXR12 (cilofexor)
     
ACCPF-05221304ACC+DGAT2NCT03776175Oct 2019
DGAT2PF-06865571
     
ACC37 (firsocostat)ASK1 + FXR; ASK1 + ACC; ASK1 + ACC + FXR; ACC + FXR; ACC + PPAR; ACC + FXR + PPAR; ACC + FXR + VascepaNCT02781584May 2020
ASK172 (selonsertib)
FXR12 (cilofexor)
PPAR1 (fenofibrate)
     
ACC37 (firsocostat)ACC + GLP-1R; FXR + GLP-1R; ACC + FXR + GLP-1RNCT03987074Jul 2020
FXR12 (cilofexor) 
GLP-1R54 (semaglutide) 
     
FXR13 (tropifexor)FXR + CCR2/5NCT03517540Sep 2020
CCR2/576 (cenicriviroc)
     
FXR13 (tropifexor)FXR + SGLTNCT04065841Apr 2022
SGLTlicogliflozin
     
ACCPF-05221304TBDTBDTBD
DGAT2PF-06865571
FXR13 (tropifexor)
KHKPF-06835919

Metabolism Targets

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Peroxisome Proliferator-Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that respond to lipid levels and modulate lipid metabolism and inflammation through transcriptional regulation. There are three PPAR isoforms, PPAR-α, PPAR-δ, and PPAR-γ, encoded by different genes and with varying expression levels depending on tissue and cell type.(16) PPAR-α is primarily expressed in tissues of high metabolic rate (e.g., liver, heart muscle, brown adipose tissue), where it modulates fatty acid transport, lipid β-oxidation, and plasma triglyceride and high-density lipoprotein (HDL) levels.(17,18) PPAR-α gene expression negatively correlates with NASH disease severity, that is, low PPAR-α levels are seen in patients with severe NASH, while resolution of the disease correlates with normalization of PPAR-α levels.(17) PPAR-δ is more broadly expressed but highest in muscle tissue, where it modulates fatty acid transport and fatty acid β-oxidation.(16,18,19) PPAR-δ agonism reduces free fatty acid levels in plasma and improves insulin sensitivity.(19,20) PPAR-δ agonism also provides anti-inflammatory effects by suppressing pro-inflammatory mediators in macrophages and Kupffer cells.(21) In addition, PPAR-δ has been implicated in stellate cell function, as it contributes to hepatic stellate cell proliferation during acute and chronic liver inflammation.(22) PPAR-γ modulates gene expression in adipocytes, resulting in increased storage of fatty acids and lower levels of fatty acids in systemic circulation.(23) This effect helps to resolve insulin resistance, as elevated free fatty acids in plasma are known to exacerbate this condition in muscle.(24)
The central role of PPARs in regulating metabolism led to the development of PPAR agonists for the treatment of hypercholesterolemia, T2DM, and dyslipidemia. More recently, the positive effects of PPAR activation on lipid metabolism and insulin resistance have raised interest in PPAR agonists as a possible therapy for NASH. Although repurposed drugs have been limited by side effects that are undesirable in a NASH population, newer agonists have the potential to become one of the first classes approved for NASH.
Fibrates are PPAR-α agonists that were developed several decades ago and are still used to treat hypercholesterolemia and dyslipidemia. One fibrate that has been studied as a potential NASH treatment is compound 1 (fenofibrate; Figure 2), an isopropyl prodrug of 2 (fenofibric acid; Figure 2), a weak PPAR-α agonist.(25) A small investigator sponsored study explored the potential of 1 (200 mg/kg daily for 48 weeks) in biopsy-confirmed NASH patients.(26) Significant reductions in aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), alkaline phosphatase (AP), and glucose were observed compared to baseline, and moderate but significant reductions in hepatocellular ballooning were detected in the follow-up biopsy. Steatosis, lobular inflammation, and fibrosis, however, were unchanged after 1 treatment. Fibrates are generally considered to be a poor option for NASH treatment as they have been associated with mild transient serum aminotransferase elevations, with rare instances of acute liver injury leading to significant hepatic fibrosis. This study did, however, support a potential role for PPAR agonists in NASH therapy by showing that a fibrate had a significant impact on NASH serum biomarkers and a modest effect on ballooning.(26)

Figure 2

Figure 2. PPAR agonists 15. EC50 values for PPAR-α, PPAR-γ, and PPAR-δ are shown.

Thiazolidinediones (TZD) are another chemical class of PPAR agonists. These compounds are selective for PPAR-γ, and several are approved for T2DM. Compound 3 (pioglitazone; Figure 2) is a potent and selective TZD PPAR-γ agonist that has been evaluated in biopsy-confirmed NASH patients (ClinicalTrials.gov identifier NCT00063622).(27−29) Eighty-four patients received 3 (30 mg daily for 96 weeks), and 80 NASH patients, matched for disease severity and demographic characteristics, received placebo. While the study did not achieve its primary end point of NASH resolution after 96 weeks, patients in the treatment group showed significant reductions in ALT, AST, GGT, and AP relative to the placebo group. Liver biopsy showed significant reductions in steatosis (−0.1 placebo; −0.8 3), lobular inflammation (−0.2 placebo; −0.7 3), and hepatocellular ballooning (−0.2 placebo; −0.4 3); modest reductions in hepatic fibrosis were not significant. While these results support the use of PPAR agonists to treat NASH patients, PPAR-γ agonists are not a preferred treatment option due to the associated adverse events. In this study, the 3-dosed participants experienced significant weight gain relative to placebo (+4.7 kg and +0.7 kg, respectively). Weight gain is a known effect of PPAR-γ agonists as they increase fatty acid retention in subcutaneous adipose tissues. In addition, in the PROactive (the prospective pioglitazone clinical trial in macrovascular events; ClinicalTrials.gov identifier NCT00174993) clinical study with 3, a higher risk of nonfatal heart failure, bone fractures, and bladder cancer were observed with the 3-treated patient group.(30)
While fibrate and TZD analogs generated clinical data suggesting a potential role for PPAR agonists in NASH, there is a need for PPAR agonists with fewer undesirable side effects. Compounds 5 (seladelpar; Figure 2) and 4 (elafibranor; Figure 2) are newer agonists that have advanced in NASH clinical trials. Compound 5 is an orally active potent and selective PPAR-δ agonist being developed by Cymabay and was in a phase 2 clinical study for NASH (ClinicalTrials.gov identifier NCT03551522).(31,32) Interim results at week 12 showed impressive reductions in liver enzymes [ALT (−37.5%) and GGT (−43.1%)] in 5-treated patients relative to the placebo group. Liver fat content, as determined by MRI-PDFF, was not affected by treatment, but based on previous clinical data from PPAR agonists, significant early reductions in steatosis were not to be expected. In November 2019, Cymabay announced that it was terminating its phase 2 study of 5 in NASH patients and its recently initiated clinical studies of 5 in subjects with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Histological assessments of the first tranche of liver biopsies revealed atypical histological findings.(33) This included histology characterized as an interface hepatitis presentation, with or without biliary injury.
Compound 4 (Figure 2) is a dual PPAR-α and PPAR-δ agonist currently being developed by Genfit for NASH and PBC(34) and is one of the most advanced NASH drug candidates. In the phase 2 study GOLDEN-505, the 120 mg dosed cohort achieved significant NASH resolution relative to placebo (19% vs 12%) using a post-hoc analysis for a modified definition of NASH resolution (ClinicalTrials.gov identifier NCT01694849).(35) Additional analysis of patients with NAS >4 at baseline found the response rate in the 120 mg group improved further relative to placebo (19% vs 9%) using an updated definition of NASH resolution. Patients dosed with 4 experienced reductions in GGT, ALT, AST, low-density lipoprotein (LDL), and plasma triglycerides, while plasma HDL levels showed a modest increase compared to placebo. In a subgroup of patients with NASH and T2DM, 4 dosing induced a significant decrease in glycated hemoglobin (HbA1c) levels, which are a measure of blood sugar. Since T2DM is a risk factor for NASH, the ability of 4 to significantly reduce HbA1c in these patients may provide additional clinical benefit. Compound 4 showed a very good tolerability and safety profile. There was a mild, reversible, but statistically significant creatinine increase in patients dosed with 4, while other renal markers, such as cystatin C and microalbuminuria, remained normal. Isolated, reversible creatinine elevations without promoting renal failure are known to occur with PPAR-α agonist 1, with possible mechanistic relation to increased skeletal muscle production. Currently 4 is in a phase 3 clinical trial evaluating its efficacy and safety versus placebo in NASH patients (RESOLVE-IT; ClinicalTrials.gov identifier NCT02704403), with expected completion in 2021. The primary outcome of this trial is evaluating the proportion of 4-treated patients relative to placebo who achieve resolution of NASH without worsening of fibrosis measured at 72 weeks. Top line interim data are expected in the first quarter of 2020.(36)

Farnesoid X Receptor

The farnesoid X receptor (FXR) is a nuclear hormone receptor that binds to bile acids and modulates metabolic pathways including bile acid synthesis, de novo lipogenesis, and glucose metabolism.(37) This receptor is highly expressed in the liver, gall bladder, intestines, and kidney.(38) Upon activation by bile acids, FXR translocates to the nucleus, heterodimerizes with the retinoid X receptor (RXR), and regulates gene transcription via hormone response elements (HRE). In the liver, FXR activation induces the expression of small heterodimer partner (SHP) protein, which functions to inhibit CYP7A1 gene transcription. CYP7A1 catalyzes the rate-limiting step in the synthesis of bile acids from cholesterol in the liver by producing 7α-hydroxycholesterol, which is the precursor to 7α-hydroxy-4-cholesten-3-one (C4).(39) SHP also negatively regulates sterol regulatory element-binding protein 1c (SREBP-1c), resulting in decreased glycerol-3-phosphate acyltransferase (GPAT) expression and reduced synthesis of triacylglycerol and glycerophospholipids.(40,41) In the intestine, FXR activation increases secretion of fibroblast growth factors FGF15 (rodent) and FGF19 (primate). FGF15 or -19 acts through the FGFR4/klotho-β pathway to inhibit CYP7A1 transcription.
Through these mechanisms, FXR regulates bile acid levels, as well as maintains homeostasis of multiple metabolic pathways. There are potential therapeutic roles for both agonists and antagonists of FXR, highlighting the complex role that this receptor plays in metabolic regulation. FXR knockout mice showed elevated bile acid levels and liver steatosis, inflammation, and fibrosis.(42,43) However, several studies have suggested that depletion or antagonism of FXR, specifically in the intestine, may have therapeutic potential in NASH.(44−46) In one study, treatment of mice with an intestine-selective FXR antagonist improved metabolic function in diet-induced and genetic obesity.(47) Nevertheless, activation of FXR with small molecule agonists is the most advanced modality and is a highly promising strategy for treating NASH, either as a standalone therapy or in combination with other agents; several FXR agonists are currently in clinical trials.
Compound 7 (6-ECDCA, obeticholic acid, OCA; Figure 3) is a steroidal FXR agonist that Intercept Pharmaceuticals has advanced to the clinic. Early studies identified 6 (Figure 3) as a moderately potent FXR agonist, and structure–activity relationship (SAR) exploration at the 6-position produced the more potent compound 7.(48−50) In early 2019, a pivotal study of compound 7 in 931 patients with noncirrhotic NASH with liver fibrosis became the first phase 3 trial for NASH showing positive results (REGENERATE; ClinicalTrials.gov identifier NCT02548351), potentially making 7 the first approved drug for NASH. This trial is a long-term study of NASH patients with stage 2 and 3 fibrosis or stage 1 fibrosis with additional risk factors, such as T2DM and obesity.(51,52) Patients were randomized to receive placebo, 10 mg of 7, and 25 mg of 7 daily through oral administration. The study showed that, following 18 months of oral treatment with compound 7 (25 mg QD), fibrosis was significantly improved (≥1 stage) with no worsening of NASH compared to placebo. Pruritus was the most common side effect for 7, potentially related to activation of G-protein-coupled bile acid receptor (TGR5).(53,54) Triglyceride levels rapidly and continually decreased in the treatment groups during the 18-month period.

Figure 3

Figure 3. Steroidal FXR agonists, compound 7 and its precursor 6, with reported EC50 values.

EDP-305 (cellular EC50 = 0.008 μM) is a potent steroidal FXR agonist that is being developed by Enanta Pharmaceuticals.(55−57) In this compound series, researchers sought to replace the carboxylic acid group of steroid-based FXR agonists to avoid the formation of taurine and glycine conjugates, two metabolites that may be associated with liver toxicity and pruritus.(56) In a phase 1 clinical trial, treatment with EDP-305 (0.5–20 mg) resulted in increased FGF19 and reduced C4 in both healthy volunteers and NAFLD patients compared to placebo treatment (ClinicalTrials.gov identifier NCT03207425). Pruritus was observed in 9% of participants treated with EDP-305 and 3% for placebo. Recently, Enanta announced positive results of a 12-week phase 2a trial (ARGON-1; ClinicalTrials.gov identifier NCT03421431).(58) The study’s primary end point was achieved with a statistically significant ALT reduction of 28 U/L in the EDP-305 2.5 mg arm versus 15 U/L in the placebo arm at week 12, and there was a significant reduction in liver fat content (MRI-PDFF responders had ≥30% fat reduction) with EDP-305 at the 2.5 mg dose. In addition, reductions in C4 and increases in FGF-19 were observed. Pruritus was present in approximately 51% of the subjects in the 2.5 mg arm compared to less than 10% in the 1 mg arm. A 72-week phase 2b study (ARGON-2) with histological end points in NASH patients is planned to initiate in 2020.
A number of nonsteroidal FXR agonists have also been explored in preclinical and clinical studies.(59) One of the first of this class was compound 8 (Figure 4), a nonsteroidal partial FXR agonist identified almost 20 years ago by screening a combinatorial library using a cell free assay.(60) Compound 8 lacked cellular potency and was optimized to produce 9 (GW-4064; Figure 4), which had greatly improved cellular activity and was a full agonist. Compound 9 fits well in the binding pocket of FXR (Figure 5), with the carboxylic acid maintaining a salt bridge with Arg331. Although 9 has limited oral bioavailability in rats (F = 10%, with a t1/2 = 3.5 h) and the stilbene moiety causes UV light instability, it continues to be widely used as a tool compound. Furthermore, all the nonsteroidal FXR agonists currently in clinical development, with the exceptions of compounds 14 and 15, are derived from compound 9.

Figure 4

Figure 4. Nonsteroidal FXR agonists (815) with reported EC50 values. Initial starting points for the optimization of these inhibitors are shown when available.

Figure 5

Figure 5. Co-crystal structure of 9 with FXR (PDB 3DCT).

Compound 10 (LY2562175, TERN-101; Figure 4) is a partial FXR agonist that was identified by Eli Lilly and Company for treating dyslipidemia; it is currently being developed by Terns Pharmaceuticals for NASH.(61) The oral bioavailability of this compound in rats, dogs, and monkeys is 21%, 82%, and 24%, respectively, and in a rat model, 10-treatment lowered LDL and triglyceride levels while elevating HDL.(62) Terns Pharmaceuticals licensed this compound in 2018 and has shown that 10 reduces liver steatosis, inflammation, ballooning, and fibrosis in a diet-induced obese mouse model of NASH.(62,63) Compound 10 is currently in a phase 1, randomized, double-blind, placebo-controlled study designed to evaluate safety, pharmacokinetics, and plasma biomarkers of FXR pathway activation, including C4 and FGF19, in participants receiving placebo or 10 at various dose levels for 7 days.(64)
Compound 12 (cilofexor; Figure 4) is a FXR agonist, initially identified by Phenex Pharmaceuticals and being developed by Gilead Pharmaceuticals.(65,66) Its precursor, 11 (Phenex Pharmaceuticals; Px-102), was tested in two phase 1 studies in healthy volunteers (ClinicalTrials.gov identifiers NCT01998659, NCT01998672). Compound 11 was shown to induce FGF19 dose-dependently, while reducing total bile acids. Safety concerns arose, however, when a trend was observed for HDL cholesterol lowering and ALT and AST elevation. To overcome the adverse effects of 11, compound 12 was identified by screening to be an intestinally biased FXR agonist.(66) In a mouse model, no changes in ALT or cholesterol were observed. Additionally, tissue-biased gene induction in the ileum was observed for 12. Though no explanation was provided, one can postulate that 12 is more polar than 11 due to the additional nitrogen atoms and hydroxyl group and thus 12 might not be absorbed as well when taken orally. This would limit systemic exposure and could contribute to restriction in the gastrointestinal tract. In a phase 1 study, 12 displayed dose-dependent induction of FGF19, but without changes in cholesterol parameters when dosed up to 100 mg QD in healthy volunteers (ClinicalTrials.gov identifier NCT02654002). In a phase 2 clinical trial, NASH patients administered 12 (30 mg and 100 mg QD) showed moderately reduced serum C4 (ca. 40%) and liver fat reduction by MRI-PDFF compared to placebo (ClinicalTrials.gov identifier NCT02854605). Incidents of pruritus were observed in the 100 mg dose group (14% vs placebo 4%).(67)
Compound 13 (tropifexor; Novartis; Figure 4) has an azabicyclo[3.2.1] core substituted with a carboxylic acid bearing a benzothiazole group to position the molecule in a very favorable conformation for FXR binding.(68) As a result, it shows high potency and efficacy in biochemical and cellular assays. Compound 13 has low clearance in rats and 20% bioavailability when formulated as a microemulsion. In 14-day pharmacokinetics/pharmacodynamics (PK/PD) studies in rodent, SHP mRNA in liver and ileum, as well as FGF15 mRNA in ileum, were induced at a dose as low as 0.3 mg/kg. Compound 13 was evaluated in a phase 2 clinical trial in patients with NASH (FLIGHT-FXR; ClinicalTrials.gov identifier NCT02855164).(69) Interim results have been disclosed that showed higher doses of 13 resulted in dose-dependent decreases in ALT, hepatic fat fraction, and body weight with good safety and tolerability after 12 weeks of treatment. Similar to other FXR agonists, 13 was associated with mild pruritus and minor dose-related increases in LDL cholesterol. Combination clinical studies are currently underway that will evaluate 12 + licogliflozin (SGLT2; ClinicalTrials.gov identifier NCT04065841) and 12 + 76 (CCR2/5; ClinicalTrials.gov identifier NCT03517540) in patients with NASH and liver fibrosis.
Compound 14 (nidufexor; Figure 4) is the second clinical compound from Novartis for NASH.(70,71) It has a different scaffold than 13 and is less potent. A 12-week phase 2 clinical trial of 14 in NASH patients measured safety end points, as well as transaminase levels. The trial was completed in 2018, but the data have not been publicly disclosed (ClinicalTrials.gov identifier NCT02913105).
Enyo Pharma is developing FXR agonist 15 (EYP001a; Figure 4), which is currently in a phase 1b clinical trial for NASH that is expected to complete in late 2019 (ClinicalTrials.gov identifier NCT03976687).(72) The 16 participants, including 4 healthy volunteers and 12 NASH patients, were assigned to three treatment arms. Two of the groups are administered once-daily oral doses of 15, and the third receives a twice-daily oral dose. The primary end points will be safety and PK assessments; secondary outcome measurements include C4, FGF19, and total bile acids. A phase 2a trial is also underway that will evaluate the safety, tolerability, PK, and efficacy of 15 in patients with NASH (ClinicalTrials.gov identifier NCT03812029).
MET409 (structure not disclosed) is a FXR agonist being evaluated for NASH by Metacrine, and recently positive phase 1 interim results were reported. Patients receiving 50 mg oral QD dosing of MET409 for 4 weeks demonstrated a 20% mean relative reduction in liver fat by MRI-PDFF, as well as improved liver function tests. In this study, no incidence of pruritus was reported.(73)

Thyroid Hormone Receptor β

Thyroid hormone plays a crucial role in the regulation of numerous physiological processes, from neurologic development to metabolism.(74) The hormone is produced in the thyroid gland, and its levels are under stringent control through a negative feedback mechanism involving hypothalamus-secreted thyrotropin releasing hormone (TRH) and pituitary gland-secreted thyroid stimulating hormone (TSH).(75,76) This process is commonly referred to as the hypothalamic–pituitary axis. Compound 17 [thyroxine (T4); Figure 6A], a prohormone, is secreted by the thyroid gland and is converted to its biologically active form, 16 [triiodothyronine (T3); Figure 6A], by regioselective deiodination catalyzed by iodothyronine deiodinases.(77) The action of 16 is mediated by two homologous nuclear receptors–thyroid hormone receptor α (THR-α) and β (THR-β).(78) THR-α is predominately expressed in the heart, brain, and skeletal muscle, whereas THR-β is found mostly in the kidney, liver, and brain. While THR-α is primarily associated with the maintenance of cardiovascular functions, THR-β controls metabolism of cholesterol and lipoproteins. Treatment of patients with 16 or 17 was shown to increase metabolic rate, reduce adiposity, and lower cholesterol; however tachycardia was observed and precludes the use of the synthetic hormones in metabolic syndrome.(78) THR-α and THR-β receptors differ by only a single amino acid in the ligand binding site (Asn331 in THR-β versus Ser227 in THR-α), and 16 has equal affinity for each subtype (Figure 6B). This has made the development of selective ligands a challenge.(79,80) Recently, THR-β has become especially interesting as a potential NASH target due to the role it plays in hepatic lipid metabolism, modulating levels of cholesterol and triglycerides, and being primarily expressed in the liver over the heart.(81,82) Two liver-targeted THR-β agonists are currently in clinical development as potential treatments for NASH.

Figure 6

Figure 6. (A) Thyroid hormone receptor natural ligands (16 and 17). (B) Overlay of 16 in THR-α (cyan; PDB 2H77) and THR-β (green; PDB 3GWS).

Compound 20 (MGL-3196, Madrigal Pharmaceuticals; Figure 7) is a THR-β-selective agonist currently in a phase 3 clinical trial for NASH. By developing a THR-β- and liver-selective compound, the researchers hoped to obtain beneficial metabolic impact without adverse heart and bone effects.(83) Previous work on THR-β-selective compounds primarily focused on close analogues of 16, varying the acid side chain and thyroid hormone mimetics.(80,84−86) Compound 18 (KB-141, Figure 7) served as an initial starting point for the development of 20.(85) Replacement of the phenol of 18 with a pyridazinone produced 19 (Figure 7). While 19 was 100-fold less potent than 18, this compound provided a reasonable starting point for further optimization of this series directed toward improving potency and selectivity. Substitution of the acetic acid of 19 with the cyano azauracil yielded 20, a potent and selective THR-β agonist. Compound 20 has good exposure and reasonable oral bioavailability (45%) in rat. In mice, treatment with 20 reduced cholesterol and liver size with no effect on heart or kidney size or bone mineral density. In a phase 1 clinical study, 20 was orally administered to healthy volunteers with mildly elevated LDL cholesterol for up to 14 days and resulted in reduction of LDL cholesterol and serum triglycerides at doses of 50–200 mg QD (ClinicalTrials.gov identifier NCT01519531).(87) Recently, the results of a phase 2b study of 20 in NASH patients were reported (ClinicalTrials.gov identifier NCT02912260).(88,89) Compound 20-treated patients showed a relative reduction of hepatic fat (primary end point) measured by MRI-PDFF compared with placebo at week 12 (−32.9% 20 vs −10.4% placebo) and week 36 (−37.3% 20 vs −8.5% placebo). NASH resolution without worsening of fibrosis occurred in 24.7% of 20-treated patients as compared with 6.5% of placebo-treated patients. In 20-treated patients who had at least 30% reduction in liver fat at week 12, NASH resolution at 36 weeks occurred in 37%. Compound 20 also showed significant effects compared with placebo in reduction of liver enzymes, atherogenic lipids, lipoprotein(a), and markers of inflammation and fibrosis. Overall, the results of this trial were positive, and a phase 3 trial has been initiated that will evaluate the efficacy and safety of 20 in patients with NASH and fibrosis (ClinicalTrials.gov identifier NCT03900429).

Figure 7

Figure 7. THR-β agonist 20 and its precursors 18 and 19. EC50 values for THR-β and THR-α in an in vitro functional assay are shown.

The second THR agonist that has advanced to the clinic is prodrug 23, which was initially identified by Metabasis Therapeutics and is being developed by Viking Therapeutics. Researchers at Metabasis focused their efforts on liver-targeted THR agonists that would retain the lipid lowering effects and show fewer side effects in extrahepatic tissues.(90) Toward this end, phosphonic acids were of interest since they are highly charged at physiological pH and generally have limited tissue distribution outside the liver and kidney. Replacement of the carboxylate of 16 (Figure 6A) with a phosphonic acid, 21 (Figure 8), led to a >100-fold decrease in binding affinity for THR-β. SAR exploration then focused on removing the primary amine, finding suitable replacements for the iodine atoms, and modifying the length and nature of the linker (phenolic ether to methylene) from the aryl ring to the phosphonic acid, which resulted in 22 (Figure 8). Compound 22 showed significant improvement in potency compared to 21. However, the highly polar nature of the phosphonic acid presented a challenge for membrane permeability and oral dosing, and a prodrug strategy was therefore developed. Three general structural classes were investigated (Figure 9), represented by cyclic phosphonate diester 23 (VK2809), acyloxymethylphosphonic diester 24, and phosphonic acid diamide 25. In a single dose efficacy model using rats fed a cholesterol rich diet, all three compounds showed an ED50 value below 1 mg/kg. Compound 23 was eventually chosen due to the highly liver-specific CYP3A-based release of 22 from this prodrug.(91,92) In a phase 1 clinical trial, 14 days of dosing with 23 (0.25–40 mg orally QD) resulted in a consistent, dose-dependent reduction in LDL cholesterol and triglyceride levels up to the 20 mg dose. No further reduction in LDL cholesterol was observed at the 40 mg dose, suggesting the maximal response had been reached. A phase 2b trial evaluated the impact of 23 on dyslipidemic parameters with NAFLD and assessed the impact on liver fat content by MRI-PDFF (ClinicalTrials.gov identifier NCT02927184). At the end of 12 weeks, reductions in liver fat were observed, with approximately 90% of patients in both the 5 and 10 mg QD dose groups achieving a liver fat reduction of ≥30% versus baseline, compared to 15% for the placebo group.(93)

Figure 8

Figure 8. THR agonist 23 and its precursors 21 and 22. Receptor binding affinity, Ki values, for THR-β and THR-α are shown.

Figure 9

Figure 9. THR agonist prodrugs of 22: 2325.

Fibroblast Growth Factors 19 and 21

Fibroblast growth factors (FGF) are peptide hormones that play important roles in development and metabolism. FGF19 regulates bile acid synthesis, lipid metabolism, and gluconeogenesis, while FGF21 modulates fatty acid levels and glucose metabolism.(94) FGF19 transcription and secretion is induced by bile acid-activated FXR.(95) FGF19 binds to the FGFR4/klotho-β receptor on hepatocytes and leads to suppression of CYP7A1 transcription. Since CYP7A1 catalyzes the rate-limiting step in bile acid synthesis, this creates a negative feedback loop that reduces secretion of bile acid into the small intestine. FGF19 has also been shown to induce expression of SHP (a transcriptional regulator) and to reduce SREBP-1c (a transcriptional activator of lipogenic genes) in insulin-treated cultured hepatocytes, suggesting additional roles in reducing plasma lipids and liver steatosis.(96) However, FGF19 can have negative outcomes as well. Chronic high exposures of FGF19 are associated with hepatic tumor development in mice, mediated by prolonged IL-6/STAT3 pathway signaling in the liver environment.(97) Tumor development in mice dosed with FGF19 could be blocked if IL-6/STAT3 signaling was interrupted by a neutralizing IL-6 antibody or JAK inhibitor. FGF21 is considered a fasting-adaptation hormone in rodents and humans and is primarily expressed by the liver in response to sustained nutrient restriction. In rodents, FGF21 induces ketogenesis, gluconeogenesis, lipolysis, and lipid β-oxidation.(98) Due to their roles in lipid metabolism, both FGF19 and FGF21, as well as their receptors, have received interest as therapeutic targets for NASH.
NGM Biotherapeutics has advanced NGM282, an analog of FGF19, into phase 2 clinical trials. This peptide is a re-engineered form of FGF19 that removes its ability to stimulate IL-6/STAT3 signaling while maintaining inhibition of bile acid synthesis.(99) In a series of spontaneous HCC mouse models, the FGF19 analog did not induce tumorigenesis, whereas mice dosed with wild-type FGF19 developed tumors.(99,100) In a 12-week phase 2a study in NASH patients, NGM282 (1 mg and 3 mg) treatment once daily by subcutaneous injection resulted in substantial reductions in liver fat content, in addition to improvements in NAS, fibrosis scores, and other markers of liver function (ClinicalTrials.gov identifier NCT02443116).(101) Plasma C4 levels were more than 90% reduced, and ALT and AST were both significantly reduced after 12 weeks of dosing with NGM282 compared to baseline. Paired pre- and post-treatment liver biopsy histologic analysis showed that the 3 mg dose cohort had histologic score changes relative to matched baseline scores of −1.1 steatosis, −0.7 ballooning, −0.5 inflammation, and −0.5 fibrosis score. Noninvasive imaging data provided complementing results to the liver biopsy data; MRI-PDFF detected an 11.2% reduction in absolute liver fat content and MRI-cT1 measured a significant reduction in hepatic inflammation at weeks 6 and 12 and 6 weeks after last dose.(102) NGM282 treatment was associated with mild gastrointestinal symptoms and LDL elevations, which were suppressed with statins.(103) NGM282 is currently in phase 2b, with estimated study completion in late 2020 (ClinicalTrials.gov identifier NCT03912532).
Several analogs of FGF21 have also advanced into clinical development. BMS-986036 (pegbelfermin, BMS) was tested in a 16-week phase 2 trial in NASH patients. Administration of the peptide by subcutaneous injection once daily resulted in significant reductions in liver fat at week 16 compared to placebo (ClinicalTrials.gov identifier NCT02413372). BMS-986036 is currently being evaluated in two other phase 2 trials: (1) BMS-986036 in patients with NASH and liver cirrhosis (ClinicalTrials.gov identifier NCT03486912) and (2) BMS-986036 in patients with NASH and stage 3 liver fibrosis (ClinicalTrials.gov identifier NCT03486899). Other FGF21 analogs are at earlier stages of development.(104) 89Bio has advanced a glycopegylated analog (BIO89-100) of FGF21 (administered once weekly by injection) to a phase 2 trial (ClinicalTrials.gov identifier NCT04048135).(105) Akero Bio is investigating once-weekly administration of a stabilized FGF21 analog (AKR-001) in NASH clinical trials (ClinicalTrials.gov identifier NCT03976401) after it was previously evaluated by Amgen for T2DM. Results of these studies are not yet available.

5′-Adenosine Monophosphate-Activated Protein Kinase

Since its discovery in 1973, 5′-adenosine monophosphate-activated protein kinase (AMPK) has been established as a master metabolic regulator, serving a key role in whole-body homeostasis.(106−109) This conserved serine/threonine protein kinase responds to the ratio of AMP/ADP/ATP within cells and is activated in response to stresses that deplete cellular ATP supplies, such as low glucose, hypoxia, ischemia, and heat shock. Activated AMPK inhibits fatty acid, triacylglyceride, and cholesterol synthesis.(110,111) In the liver, activated AMPK both inhibits fatty acid synthesis and stimulates fatty acid oxidation by phosphorylating and inactivating the downstream target acetyl-CoA carboxylase (ACC).(112,113) AMPK is also activated by exercise, suggesting small molecule activators of this enzyme could have potential benefits. AMPK is a multi-subunit complex, consisting of a catalytic α-subunit (two isoforms), a scaffolding β-subunit (two isoforms), and a regulatory γ-subunit (three isoforms); the subunits are encoded by seven genes that give rise to 12 possible heterotrimeric combinations.(114,115) Intertissue and interspecies variation in AMPK heterotrimers can make translation from preclinical models to the clinic challenging.(116) The complexity of this enzyme has also made it difficult to develop potent and selective activators, as well as to elucidate the role of AMPK in various disease states. Current drug development of AMPK activators has been recently reviewed in detail,(109) and we highlight a few compounds. It should be noted that most of the direct AMPK activators identified bind more tightly to β1-containing than to β2-containing AMPK complexes and no β2-selective activators have been produced to date. Therefore, it has yet to be determined if β1-selective or β2-selective would be preferred for addressing a particular disease state.
Several preclinical studies using small molecules have implicated AMPK as a potential target for NAFLD and NASH. Compound 27 (A-769662; Figure 10), the first direct AMPK activator developed, was shown to reduce de novo lipogenesis in rodent models.(117) More recently, Pfizer disclosed compound 29 (PF-06409577; Figure 10), a potent β1-isoform-selective AMPK activator.(118) Initial therapeutic interest for this compound was for diabetic nephropathy, but 29 was subsequently shown to correct NAFLD in rodent and primate models.(119) In both mouse and monkey preclinical models, compound 29 decreased hepatic and systemic lipids, as well as decreased cholesterol levels. Compound 29 was developed from initial high throughput screening hit indazole 28 (Figure 10), a weak activator of the α1β1γ1 isoform comparable to the natural ligand AMP. Using overlays of compounds 27 (Figure 10) and 28 as a guide, coupled with SAR studies, the Pfizer team identified β1-isoform-selective compound 29. A crystal structure of the α1β1γ1 isoform of AMPK cocrystallized with 29 revealed that it binds in the “allosteric drug and metabolite site” (ADaM). Key hydrogen bonding interactions were observed between Lys29 and the carboxylic acid group, Asp88 and the indole nitrogen, and Lys31 and Gly19 and the tertiary alcohol (Figure 11).

Figure 10

Figure 10. Structures of direct AMPK activators (27, 29, 3133) with reported EC50 values. Initial starting points for the optimization of these inhibitors (when known) are shown (26, 28, 30).

Figure 11

Figure 11. Key hydrogen-bonding interactions of the α1β1γ1 isoform of AMPK with 29 (PDB 5KQ5).

Pan-activators (targeting β1 and β2 isoforms) of AMPK have been developed by Merck.(120,121) While high throughput screening campaigns were unsuccessful at identifying a viable lead, a high concentration screen of a fragment-like library resulted in compound 30 (Figure 10). Detailed SAR studies, particularly around the alkyl carboxylic acid and aryl substitution on the benzimidazole core resulted in 31 (MK-3903; Figure 10). While this compound had low bioavailability in mice (F = 8%), oral bioavailability was improved in rats and dogs (F = 27–78%). Compound 31 was shown to reduce plasma insulin in a mouse model, but not in other rodent models. Since 31 preferentially distributes to the liver compared to muscle, it was hypothesized that activation of skeletal muscle AMPK would provide greater efficacy in resolving hyperglycemia in a T2DM indication. Toward this end, the carboxylic acid moiety, a key organic anion transporting protein (OATP) recognition element for liver uptake, was replaced, and sugar-based 32 (MK-8722; Figure 10) was identified. This compound did indeed show a robust reduction of glucose in rodent models compared to a liver-selective AMPK activator. A follow-up study revealed glycogen accumulation and increased heart weight upon extended treatment of mice and non-human primates with 32.(122) After 8 months of dosing in rhesus monkey, possible hypertrophy was detected by electrocardiogram (ECG). Otherwise the ECG was normal and may suggest that these effects are similar to those observed in elite athletes, who have exercise-activated AMPK. Although these pan-isoform AMPK activators have been investigated for application to T2DM, their usefulness for NASH has not been characterized.
To date, only one direct AMPK activator, PXL770 (Poxel), has advanced to the clinic for NASH. PXL770 has been reported as a potent and direct AMPK activator that is selective for the β1 isoform (β1 EC50 = ∼0.05 μM, β2 EC50 = 1 μM).(123) In preclinical studies, PXL770 was shown to improve liver steatosis and NAS in a diet-induced obesity mouse model of NASH.(124) In addition to decreasing adipose tissue and liver inflammation in this model, improvement in fibrogenic gene expression was also observed. In a phase 1 study, PXL770 was well tolerated, and no cardiac issues were observed (ClinicalTrials.gov identifier NCT03395470). Currently PXL770 is in a phase 2a study with NAFLD patients where the end point will be change in liver fat based on MRI-PDFF (ClinicalTrials.gov identifier NCT03763877). The structure of PXL770 has not been disclosed but may resemble compound 33 (Figure 10) and be similar to early Abbott direct AMPK activators such as 27.(125,126)

Acetyl-CoA Carboxylase

Acetyl-CoA carboxylase (ACC) is a biotin carboxylase that plays a key role in regulating fatty acid metabolism.(127) This enzyme catalyzes the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA.(128) Malonyl-CoA is both a rate-limiting substrate for de novo lipogenesis and a negative regulator of long-chain fatty acid β-oxidation through inhibition of carnitine palmitoyltransferase I (CPT-1). There are two isoforms of ACC (ACC1 and ACC2) that have distinct tissue locations and metabolic functions.(128,129) ACC1 is located in the liver, adipose tissue, and mammary gland, whereas ACC2 is primarily expressed in skeletal and heart muscle. While there has been work toward developing selective ACC1 and ACC2 inhibitors,(130−133) the most advanced compounds target both isoforms. Inhibiting ACC would be expected to decrease hepatic de novo lipogenesis and increase fatty acid oxidation, potentially reducing the accumulation of lipids in liver and improving insulin sensitivity in NAFLD.(134−136) Here we will highlight several ACC inhibitors that have progressed to the clinic for NAFLD and NASH.
Compound 34 (MK-4074; Figure 12A), a potent ACC1 and -2 dual inhibitor, was discovered and developed by researchers at Merck.(137) This compound is a substrate of the hepatocyte-specific OATP transporters, making it liver-specific. In mouse models, 34 was shown to significantly reduce de novo lipogenesis, as well as significantly reduce triglycerides in the context of hepatic steatosis.(137) A phase 1 study in NAFLD patients evaluated changes in liver fat (as measured by MRI-PDFF) following multiple doses of 34 compared to the antidiabetic drug pioglitazone (ClinicalTrials.gov identifier NCT01431521). In the 34-treated group, hepatic fat was reduced by 36%, compared to an 18% reduction for patients treated with pioglitazone. A surprising observation was that plasma triglycerides increased (now understood to be mechanism based)(137) in patients treated with 34, but not in the pioglitazone group. These findings of elevated plasma triglycerides will most likely preclude liver-specific 34 from further development.

Figure 12

Figure 12. Structures of ACC inhibitors with their reported IC50 values for ACC isoform inhibition in biochemical assays: (A) 34, (B) 35, (C) 36, (D) co-crystal structure of 36 with ACC (PDB 5KKN), (E) 37, and (F) 38.

Compound 37 (firsocostat, Figure 12E) was identified by Nimbus Therapeutics and later acquired by Gilead for the treatment of NASH. In contrast to previous ACC inhibitors that target the ACC carboxyltransferase domain (CTD), researchers at Nimbus sought to identify an allosteric inhibitor binding the biotin carboxylase (BC) domain. Allosteric inhibitors were expected to have better physicochemical properties by targeting a shallow hydrophilic pocket on the BC domain where ACC is phosphorylated by AMPK.(138) A virtual screen of the ACC2 BC domain identified 37 (Figure 12B), which was confirmed through a cocrystal structure with human ACC2 BC to bind the allosteric site (Figure 12D). A crystal structure of the carboxamide of 37, compound 36 (Figure 12C), was obtained and suggested the potency of this series can be partly attributed to filling a narrow, deep pocket near Val587 and Tyr683 (Figure 12D). In rat, 37 has oral bioavailability of 37% and good aqueous solubility. A chronic in vivo efficacy study of 37 in Zucker diabetic fatty (ZDF) rats showed a dramatic and dose-dependent reduction of hepatic triglycerides (up to 64%), hepatic free fatty acids (up to 60%), and hepatic cholesterol (up to 32%) relative to vehicle-treated animals. Compound 37 has progressed to the clinic for evaluation in NASH. In a randomized, placebo-controlled phase 2 study, the safety and efficacy of 37 was investigated in NASH patients who had baseline hepatic steatosis of at least 8% (based on MRI-PDFF) and liver stiffness of at least 2.5 kPa or who had biopsy-confirmed NASH with or without F1–F3 fibrosis (ClinicalTrials.gov identifier NCT02856555).(139) A decrease in MRI-PDFF of at least 30% from baseline occurred in 48% of patients given 20 mg of 37, 23% given 5 mg of 37, and 15% given placebo. There was also a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 (TIMP1) in patients given 37; however, there was no difference in liver stiffness between the groups. Similar to 34, increases of plasma triglycerides were also observed with patients given 37 but could be mitigated by treatment with the fibrate PPAR-α agonist 1. A combination trial of 37 and FXR agonist 12 (Gilead) has also been conducted (ClinicalTrials.gov identifier NCT02781584).(140) Twenty patients with NASH received 37 (20 mg) and 12 (30 mg), alone or in combination, orally once daily for 12 weeks. Combination therapy resulted in significantly greater reductions in liver fat, ALT, GGT, and hepatic de novo lipogenesis compared to the monotherapies. The combination of 37 and 12 also led to improvements in hepatic steatosis, liver stiffness, liver biochemistry, and markers of fibrosis in NASH. The drugs were safe and well tolerated. Other combinations will also be explored in this trial: 37 + ASK1 inhibitor 72, 37 + 12 + 72, 37 + triglyceride-reducing drug Vascepa, and 37 + 1 + 12.
PF-05221304 is an ACC inhibitor from Pfizer that has entered phase 2 clinical trials. The structure of PF-05221304 has not been disclosed but may resemble spirocycle 38 (Figure 12F).(141−143) Recently, data were disclosed for a phase 1 study that evaluated the safety, tolerability, and PK following administration of single and repeated doses of PF-05221304 in healthy adult subjects (ClinicalTrials.gov identifier NCT02871037). PF-05221304 was well tolerated at all doses, and exposure was dose proportional. In addition, fructose-stimulated hepatic de novo lipogenesis was inhibited in a dose-dependent manner. A phase 2a study has been completed that evaluated PF-05221304 in NAFLD patients (ClinicalTrials.gov identifier NCT03248882) and showed a marked effect on liver fat and ALT with potential for an acceptable safety profile with PF-05221304 doses above 2 mg QD and below 25 mg QD. Increased circulating triglyceride levels were also observed that are a now recognized as a mechanistic consequence of hepatic ACC inhibition. In late 2018, Novartis announced a collaboration with Pfizer to evaluate combinations of the Novartis FXR compound 13 with one or more Pfizer compounds for the treatment of NASH.(144) This included ACC inhibitor PF-05221304, a DGAT2 inhibitor (PF-06865571), and a KHK inhibitor (PF-06835919).

Diacylglycerol O-Acyltransferase

Triglycerides are a major source of dietary energy and are essential for normal physiological function.(145) Their overaccumulation in adipose and nonadipose tissues results in obesity and a variety of human diseases.(146) Two major pathways for triglyceride biosynthesis have been identified: the glycerol phosphate pathway (Kennedy pathway) and the monoacylglycerol (MAG) pathway.(147,148) The glycerol phosphate pathway is responsible for de novo synthesis of triglycerides by sequential esterification of the hydroxy groups. The MAG pathway includes re-esterification of partial glycerides, which originate from the hydrolysis of triglycerides.(149) The final and only committed step common to both pathways is the conversion of diacylglycerol to triglyceride by diacylglycerol O-acyltransferase (DGAT).(150) There are two isoforms of this enzyme, DGAT1 and DGAT2, which have different tissue distributions and functions;(151−153) DGAT1 is highly expressed in the small intestine and DGAT2 in the liver.(152−154) The two isoforms also show differences in response to substrate levels.(155,156) When MAG concentrations are high, DGAT1 activity is significantly inhibited, resulting in increased production of diacylglycerol; DGAT2 is not sensitive to MAG levels. DGAT1 knockout mice show numerous beneficial metabolic phenotypes, including resistance to diet-induced obesity, increased sensitivity for both insulin and leptin, and prolonged release of glucagon-like peptide 1 (GLP-1, gut hormone that promotes insulin secretion) along with delayed gastric emptying.(154,157) In contrast, DGAT2 knockout animals die soon after birth.(158) Studies using antisense oligonucleotides and overexpression have elucidated a role for DGAT2 in regulating very low density lipoprotein (VLDL) secretion, triglyceride levels, and hepatic lipid burden.(158,159) With these studies in hand, many companies became interested in developing inhibitors for DGAT1 and DGAT2 for the treatment of metabolic disorders and other disease states related to triglyceride synthesis.(160,161)
The first DGAT inhibitors to enter the clinic targeted DGAT1 for the treatment of T2DM and obesity.(161) Unfortunately, these compounds had significant gastrointestinal adverse effects that are believed to be related to the mechanism of action. Dose escalation was often limited by nausea, vomiting, and diarrhea. In one study with 39 (AZD7687; Figure 13),(162) these effects were shown to be related not only to dose but also to the fat content of recent meals.(163) This led the authors to conclude that the side effects of DGAT1 inhibitors are directly related to perturbation of lipid handling in the gut and may not be a suitable treatment for NASH.

Figure 13

Figure 13. DGAT inhibitors (3941) with their reported IC50 values for DGAT isoform (when known) inhibition in biochemical assays.

While there has been less work on developing DGAT2 inhibitors, several are currently in clinical trials. Lilly has completed a phase 1 trial of LY3202328 in overweight otherwise healthy participants and those with dyslipidemia to evaluate its safety and tolerability (ClinicalTrials.gov identifier NCT02714569); no results for this study have been disclosed. The structure of LY3202328 has not been reported, but compounds represented by 40 (Figure 13) have been disclosed.(164,165) DGAT2 inhibitor PF-06865571 (Pfizer), also without a reported structure but possibly resembling 41 (Figure 13),(166) has progressed to clinical studies for the treatment of NAFLD and NASH. Several phase 1 studies have been completed, but results have not yet been disclosed. In one phase 1 study, NAFLD patients were treated for 2 weeks (50 or 300 mg dose) and changes from baseline in whole liver fat were measured (ClinicalTrials.gov identifier NCT03513588). A phase 2 study is ongoing to evaluate PF-06865571 alone or in combination with the Pfizer ACC inhibitor PF-05221304 in NAFLD patients (ClinicalTrials.gov identifier NCT03776175). The antisense oligonucleoside IONIS-DGAT2Rx, developed by Ionis, completed a phase 2 trial in patients with T2DM (ClinicalTrials.gov identifier NCT03334214) to evaluate the effect of DGAT2 inhibition on the reduction of hepatic steatosis (measured by MRI-PDFF).(167) Treatment with IONIS-DGAT2RX resulted in a significant absolute reduction in liver fat of −5.37% compared to −0.04% in patients treated with placebo. In treated patients, 50% had at least a 30% relative reduction in liver fat. Importantly, liver fat reduction was not accompanied by hypertriglyceridemia or gastrointestinal side effects, and there were no elevations in serum transaminases, plasma glucose, or body weight.

Fatty Acid Synthase

Fatty acid synthase (FASN) catalyzes the conversion of malonyl-CoA and acetyl-CoA to palmitate. Palmitate is the first fatty acid produced and is the precursor to longer more complex fatty acids.(168,169) In many cancers, fatty acid synthesis is upregulated and fuels tumor growth, making FASN a target of interest for oncology.(170−172) FASN has also become of interest for NASH due to the role it plays in de novo lipogenesis and its involvement in the activation of PPAR-γ, a nuclear hormone receptor involved in lipid and glucose metabolism.(173) In patients with NAFLD, high levels of FASN expression in the liver were shown to correlate with a higher degree of hepatic steatosis, although not with inflammation or hepatocyte ballooning.(174)
Recently, Ascletis Pharma has initiated a phase 2 trial of an orally bioavailable FASN inhibitor, 42 (ASC40, TVB-2640; Figure 14), in patients with NASH.(170,175) This compound has previously been evaluated for oncology indications and is in phase 2 trials in patients with HER2 positive breast cancer. In the NASH clinical trial, the effect of 42 on hepatic fat fraction will be determined (ClinicalTrials.gov identifier NCT03938246). NASH patients will also be monitored for levels of plasma triglycerides, liver enzymes, and inflammatory and fibrotic biomarkers. Forma Therapeutics has also progressed a FASN inhibitor, FT-4101, into the clinic. FT-4101 is described as a potent, selective oral small molecule inhibitor of FASN that systemically targets steatosis and inflammation in patients with NASH.(176) In a phase 1 clinical study, FT-4101 was shown to be safe and well tolerated and significantly reduces hepatic de novo lipogenesis in overweight or obese patients (ClinicalTrials.gov identifier NCT04004325).(177)

Figure 14

Figure 14. FASN inhibitor (42).

Mitochondrial Pyruvate Carrier

Mitochondrial pyruvate carrier (MPC) is an emerging target for NASH.(178,179) This protein is involved in pyruvate entry into the mitochondria and serves as the main connection between nonoxidative and oxidative metabolism.(180) The possibility of targeting MPC for metabolic disorders such as NASH arose from studies of the antidiabetic drugs TZDs (examples 44 [rosiglitazone] and 3; Figure 14). Mechanistically, TZDs act through PPAR-γ and regulate the transcription of genes related to lipid and glucose metabolism.(181−183) Photoaffinity cross-linking studies with a TZD probe, however, suggested additional targets of TZD and identified two proteins closely related to each other, MPC1 and MPC2.(182−184) Later studies showed that TZDs are in fact potent and selective inhibitors of facilitated pyruvate transport into mitochondria in a number of different cell types.(185) Several preclinical studies in rodents have hinted that MPC may be a viable target for NAFLD/NASH. One study found that expression of MPC proteins increased in animals given a high fat diet.(186) In addition, selective knock out of either mpc1 or mpc2 in the liver parenchymal cells of mice protected against liver damage induced by a high fat diet.(187,188)
Compound 43 (MSDC-0602K, MSDC-0602; Figure 15) is being developed by the Metabolic Solutions Development Company as a treatment for NASH and liver fibrosis.(183,184,189) Since PPAR-γ inhibitors are associated with weight gain,(190) the researchers aimed to identify a TZD-like compound that selectively targeted MPC. Their efforts led to 43, which has significantly reduced PPAR-γ activity when compared to approved TZD inhibitors 44 and 3 (Figure 15). Additionally, 43 bound to mitochondrial membranes with similar affinity as 44 and 3. Compound 43 was shown to prevent and reverse liver fibrosis and to suppress expression of stellate cell activation markers in livers of mice fed a diet rich in trans-fatty acids, fructose, and cholesterol.(188) Results from the EMMINENCE phase 2b trial were recently disclosed.(191) In this trial, 43 was evaluated in patients with NASH, with a primary end point of a two-point reduction in NAS (ClinicalTrials.gov identifier NCT02784444). The primary analysis showed dose-dependent trends toward improvement in NAS reduction by 2 or more points and NASH resolution. In the post hoc analysis (using the qualifying baseline read and imputing missing data as a treatment failure), statistical significance was observed at the 250 mg level in >2 point improvement in NAS and NASH resolution with >2 point reduction in NAS. In addition, a significant improvement in the levels of liver enzymes was also observed for patients treated with 43 compared to placebo. A phase 3 study is planned that will evaluate 43 in patients with NASH and diabetes, assessed for resolution of NASH and improved glycemic control. Primary outcome measures will be mean change in HbA1c from baseline and biopsy-confirmed hepatic histological resolution of NASH (ClinicalTrials.gov identifier NCT03970031).

Figure 15

Figure 15. MPC- and PPAR-γ-targeting compounds (43, 44, and 3). Binding to mitochondrial membranes (indicating MPC1/2 interactions) and activity against PPAR-γ in a biochemical assay are shown.

Ileal Bile Acid Transporter

After secretion into the gastrointestinal tract, bile acids play an essential role in digestion and absorption of fat, nutrients, and lipid-soluble vitamins.(192,193) As bile acids move through the small intestine, about 95% are reabsorbed into enterocytes via the ileal bile acid transporter (IBAT; also known as the apical sodium-dependent bile acid transporter [ASBT]) and recirculated to the liver in a process called enterohepatic circulation.(194) The accumulation of bile acids in the liver has been shown to play a major role in metabolic syndromes including NAFLD/NASH, suggesting that an IBAT inhibitor might be useful in treating these diseases.(192) Preclinical studies with IBAT inhibitor 45 (SC-435; Figure 16)(195,196) indicated a role for this target in the development of NAFLD. In mice fed a high-fat diet, treatment with 45 reduced hepatic triglyceride and total cholesterol concentrations and showed a protective effect against NAFLD.(197) In addition, 45 was found to induce mRNA expression of bile synthesis genes in the liver and reduce mRNA expression of ileal bile acid-responsive genes.

Figure 16

Figure 16. IBAT inhibitors (4547) with their reported IC50 values.

One IBAT inhibitor that has been investigated in the clinic for NASH is 46 (volixibat; Figure 16), described as a highly potent, minimally absorbed, competitive inhibitor.(198) Originally identified by researchers at Sanofi Aventis, this compound was progressed by Shire. A phase 1 study evaluated 46 in overweight and obese adults and showed a significant increase in fecal bile acid secretion, reflecting the expected inhibition of bile acid reabsorption (ClinicalTrials.gov identifier NCT02287779). Compound 46 moved into a phase 2 trial to evaluate its safety and efficacy in patients with NASH and was given an FDA fast track designation (ClinicalTrials.gov identifier NCT02787304). The trial was to investigate a primary end point of reduction of at least two points from baseline NAS, without worsening of fibrosis. However, in mid-2018, Shire announced that the phase 2 trial had been discontinued, with no information disclosed.
Currently the only drug in this class that is still being evaluated for NASH in the clinic is 47 (elobixibat; Figure 16). Compound 47, developed by Albireo Pharma, is a potent and selective IBAT inhibitor.(199) This compound displays >450-fold selectivity for IBAT over the liver sodium-dependent bile acid transporter and >9000-fold selectivity over the neutral amino acid transporter. A phase 2 study is currently recruiting to evaluate the efficacy and safety of 47 compared to placebo in adults with NAFLD or NASH (ClinicalTrials.gov identifier NCT04006145). One outcome measurement will be liver fat by MRI-PDFF. This trial is expected to be completed during the first half of 2020.

Ketohexokinase

High fructose consumption (such as from soft drinks) has been implicated in obesity, increased blood pressure, T2DM, hepatic steatosis, and NAFLD.(200−205) In contrast to glucose liver metabolism, which is tightly regulated, fructose is rapidly phosphorylated by ketohexokinase (KHK) to fructose-1-phosphate without feedback inhibition.(206) KHK is highly expressed in the liver, kidney, and brain and found at lower levels in many other tissues.(207) Fructose metabolism can alter normal lipid metabolism in the liver by increasing levels of pyruvate and consequently acetyl-CoA, which serves as a substrate to produce long-chain fatty acids for gluconeogenesis and de novo lipogenesis.(208) Recently it has been shown that patients on a high-fructose diet have both increased de novo lipogenesis and higher liver fat.(209)
Several studies have identified KHK as a key driver of the adverse effects of fructose. KHK-knockout mice on a high fructose diet are protected from fructose-induced metabolic syndrome and are less prone to developing fatty liver as compared to wild-type mice.(207,210) Furthermore, in aldolase B-knockout mice (an enzyme upstream from KHK), inhibition of KHK can prevent the hypoglycemic shock, liver inflammation, and intestinal damage caused by exogenous fructose, demonstrating the importance of KHK in the pathogenesis of fatty liver and steatohepatitis.(211) In humans, hepatic KHK deficiency results in a benign condition called essential fructosuria characterized by unmetabolized fructose being excreted in the urine.(212) Taken together, these studies suggest that KHK is a viable drug target for NASH.
Several KHK inhibitors have been reported in the literature, but so far only one compound (PF-06835919) being developed by Pfizer has progressed to clinical trials for NASH.(213−216) Compound 50 was developed from a fragment-based drug discovery approach (Figure 17). Key to the development of 50 was to identify a compound that could be used as a tool in rodent, as earlier compounds were very limited in this regard due to poor potency against rat KHK. The researchers hypothesized that identifying a nonbasic moiety that interacts with Asp27 (serine in rat KHK) could decrease the potency difference between rat and human KHK. Initial fragment hits (examples 48 and 49 in Figure 17) contained a heteroaromatic core. Co-crystallization of the fragments with KHK revealed that many fragments had similar binding modes, and subsequent similarity searches resulted in compounds with increased potency. Further hybridization of these hits from the similarity search, parallel chemistry, and structure-based drug design resulted in 50. Compound 50 was moderately potent, highly selective, and, importantly, equipotent against both rat and human KHK. A cocrystal structure of 50 with human KHK revealed that this compound does not interact with Asp27, but rather the dihydroxy pyrrolidine interacts with Glu227 and Asn107 (Figure 18). Compound 50 demonstrated favorable ADME, safety profile, and good exposure in rats. In a rat model of KHK inhibition, 50 was shown to decrease the metabolism of fructose. The structure of PF-06835919 has not been disclosed, but Pfizer has recently published a patent disclosing bicycle structures represented by compound 51 (Figure 17) that display a significant increase in potency compared to compound 50.(217)

Figure 17

Figure 17. Structures of KHK inhibitors (50 and 51) with their reported IC50 values. Examples of starting fragments for the optimization of these inhibitors (48 and 49) are also shown.

Figure 18

Figure 18. Co-crystal structure of 50 with human KHK [PDB 5WBZ].

A phase 2a study of PF-06835919 in patients with NAFLD has been completed (ClinicalTrials.gov identifier NCT03256526). Administration of the compound for 6 weeks reduced whole liver fat as measured by MRI-PDFF in subjects with NAFLD.(218) Favorable trends were also observed for markers of target engagement (e.g., urinary fructose), insulin resistance, and inflammation (e.g., adiponectin). PF-06835919 was well tolerated in these patients. Currently underway is a phase 2 clinical study evaluating the safety, tolerability, and pharmacodynamics of PF-06835919 administered daily for 16 weeks in patients with NAFLD and T2DM on metformin (ClinicalTrials.gov identifier NCT03969719).

Glucagon-like Peptide-1 Receptor

One of the most promising targets for the potential treatment of NASH is the glucagon-like peptide-1 receptor (GLP-1R).(219−221) The natural endogenous ligand, glucagon-like peptide-1 (GLP-1), is one of the major gut hormones (otherwise known as incretins) and promotes insulin secretion from pancreatic β-cells in a glucose-dependent manner following food ingestion.(222−224) The half-life of GLP-1 in circulation is very short, on the order of less than 2 minutes. Its rapid inactivation is primarily due to the proteolytic enzyme dipeptidyl peptidase-4 (DPP-4), which cleaves two amino acids from the GLP-1 N terminus.(225)
Early studies with the administration of exogenous GLP-1 to patients showed improved glucose homeostasis, decreased gastrointestinal motility (gastric emptying), decreased food intake, and enhanced satiety that ultimately led to weight loss.(226−228) This suggested that synthetic, long-lasting GLP-1R agonists might provide a similar benefit, which led to the development of GLP-1 peptides with reduced susceptibility to DPP-4 degradation.(229) Currently, several GLP-1R agonists are approved to help T2DM patients manage glycemic control (including 52 [exenatide, Astra Zeneca], 53 [liraglutide, Novo Nordisk], and 54 [semaglutide, Novo Nordisk]) (Figure 19).(230) Overall these drugs are safe and quite efficacious and are becoming one of the foundations for treatment of T2DM and obesity.(231) Although none of these agonists have been approved for NASH, several are currently being investigated for this indication.

Figure 19

Figure 19. Structures of peptide GLP-1R agonists (5254).

Compound 52 (Figure 19), which was developed from the venom of the Gila monster, was the first approved GLP-1R agonist (launched in 2005).(232) The 39-amino acid peptide, called extendin-4, shows 53% sequence identity to human GLP-1 and is resistant to DPP-4 degradation due to an alanine-to-glycine substitution.(233,234) Several trials have examined the use of 52 in patients with NAFLD. A small (eight subjects) phase 2/3 study in T2DM patients with proven NAFLD assessed 28 weeks of twice-daily treatment with 52 (ClinicalTrials.gov identifier NCT00650546).(235) Of the eight patients treated, three met the primary end point of improved liver histology (based on NAS before and after therapy) and four subjects saw an improvement in fibrosis. Additionally, a decrease in mean body weight, as well as an improvement in HbA1c and ALT, was observed. A second study compared the efficacy of 52 versus metformin in patients with NAFLD and T2DM.(236) A reduction of body weight and an improvement in liver enzymes were observed for both drugs, with 52 being more effective.
Compound 53 (Figure 19) has been one of the most widely studied GLP-1R agonists for NASH. Compound 53 has higher amino acid identity to GLP-1 than 52 (97% vs 53% for 52), as well as a lysine to arginine substitution at position 34 that confers resistance to DPP-4 degradation and allows for once-daily dosing.(237) In the phase 2 study LEAN (Liraglutide Efficacy and Action in NASH), 52 NASH patients were randomized and assessed with 53 treatment (1.8 mg/day) over 48 weeks compared to placebo (ClinicalTrials.gov identifier NCT01237119).(238) It was found that 39% of 53-treated patients (compared to 9% in placebo group) achieved histological resolution of NASH. Significant reduction in the worsening of fibrosis was also observed for the 53-treatment group. One key observation was that weight loss was similar in patients with improved liver histology and those without, suggesting that the beneficial effects of GLP-1R agonists may not be due entirely to body weight reduction. Another phase 2 study compared 53 to insulin on liver fat fraction, as measured by MRI-PDFF, in T2DM patients (ClinicalTrials.gov identifier NCT01399645).(239) Similar glycemic control and hepatic fat burden was observed for both drugs, but a reduction in body weight was observed only for the 53-treated group. In a phase 4 study, 87 patients with NAFLD and T2DM were treated with either metformin, gliclazide, or 53 (ClinicalTrials.gov identifier NCT03068065).(240) Similar reductions in intrahepatic fat were observed for the metformin and 53 groups, while gliclazide was less effective. Currently, a phase 3 study is underway that will compare the efficacy and safety of 53 to lifestyle modification and bariatric surgery for weight loss and reducing the severity of NASH (ClinicalTrials.gov identifier NCT02654665).
Compound 54 (Figure 19) was developed as a once-weekly GLP-1R agonist. It has two substitutions (lysine-to-arginine at position 34 and alanine-to-α-amino-isobutyric acid at position 8) and a modification of lysine 26 with a C-20 diacid; these promote stability and result in a half-life of 165 h.(241) Two phase 2 trials of 54 are currently in progress. The NAFLD HEROES (hepatic response to oral glucose, and the effect of semaglutide) trial will measure hepatic steatosis using MRI-PDFF in NAFLD patients treated with 54 (ClinicalTrials.gov identifier NCT03884075). The second trial will investigate the efficacy and safety of 54 once daily versus placebo in subjects with NASH (ClinicalTrials.gov identifier NCT02970942). In April 2019, Gilead announced a collaboration with Novo Nordisk for a trial combining 54 with their respective pipelines in NASH.(242)
While most GLP-1R agonists in development are peptides, several companies have disclosed nonpeptidic, small molecule GLP-1R agonists.(243) Several small molecules are in or approaching the clinic and are being investigated for T2DM. It would be assumed, however, that they will also be evaluated for NASH in the near future.
vTv Therapeutics (formerly TransTech Pharma) is pursuing clinical studies of TTP273, which they describe as an oral, small molecule GLP-1R agonist for the treatment of T2DM. The disclosed structures of this chemical series are represented by oxadiazoanthracene 55 (Figure 20).(244) These compounds are reported to be noncompetitive, allosteric agonists and may function by a distinct mechanism compared to the peptide agonists.(245) While GLP-1R peptide-based agonists affect both the G-protein and β-arrestin pathways, TTP273 does not appear to signal through β-arrestin. This could potentially lead to a distinct safety profile compared to the peptide agonists. In preclinical studies, TTP273 was shown not to be brain penetrant and yet still has an effect on food intake that is believed to be mediated by neuro-enteroendocrine signaling.(246) TTP273 has completed a phase 2 study in patients with T2DM where it demonstrated a statistically significant reduction in HbA1c and showed trends toward weight loss; the compound was well-tolerated, with negligible incidences of nausea and vomiting (ClinicalTrials.gov identifier NCT02653599).(247−249)

Figure 20

Figure 20. Structures of GLP-1R agonists (55, 56, and 58) with their reported EC50 values. An example of an optimization starting point is also shown (57).

OWL833 is a preclinical small molecule GLP-1 agonist that is being studied for the treatment of T2DM. The compound series, represented by compound 56 (Figure 20), was first disclosed by Chugai in 2018.(250) In September of that year, Lilly entered into a license agreement for OWL833. In preclinical studies, OWL833 was shown to improve glucose tolerance and reduce food intake in cynomolgus monkeys at levels similar to 52.(251) The compound is now ready to enter phase 1 studies.
The most recently disclosed small molecule GLP1-R agonist is compound 58 (PF-06882961; Figure 20) from Pfizer, which is described as an orally available allosteric agonist.(252) An initial high throughput screening hit (57; Figure 20) had minimal activity but was optimized with SAR studies focused on potency, hERG activity, and solubility to ultimately yield 58. Interestingly, this compound is not active in mouse and rat but was active in non-human primates where it was shown to be efficacious by reducing food intake, increasing plasma insulin, and reducing plasma glucose compared to vehicle.(253) Compound 58 has completed two phase 1 trials evaluating PK, safety, and tolerability (ClinicalTrials.gov identifiers NCT03492697 and NCT03309241). A third phase 1 is underway, which is a dose-escalating study in patients with T2DM (ClinicalTrials.gov identifier NCT03538743). A 16-week phase 2 is planned to further evaluate the efficacy and safety in T2DM patients (ClinicalTrials.gov identifier NCT03985293).

Sodium-Dependent Glucose Cotransporters

Since the discovery that 59 (phlorizin; Figure 21), a natural product in apple tree bark, inhibits the sodium-dependent glucose cotransporters (SGLTs), several drugs that target this transporter have come to the market for diabetes.(254,255) SGLTs are a family of transporters that move glucose across cellular membranes.(256) Several isoforms of this transporter exist and are tissue specific.(257) SGLT1 is primarily found in intestinal enterocytes of the small intestine, where it is responsible for intestinal absorption of glucose.(258,259) This isoform is also present in the convoluted (renal cortex) segment of the kidney proximal tubule, where it absorbs glucose from the blood. SGLT2 is mainly expressed in the straight (descends into the outer medulla) segment of the kidney proximal tubule and is also responsible for glucose reabsorption.(260) Humans with a SGLT1-inactivating mutation experience glucose malabsorption with diarrhea, dehydration, and minimal glucosuria. In contrast, individuals with a SLGT2-inactivating mutation have pronounced renal glucosuria but are otherwise healthy.(260−262) SGLT inhibitors have had significant impact for the treatment diabetes.(263−266) SGLT2-selective inhibitors are preferred due to their ability to lower blood sugar with selectivity for kidney reabsorption. Currently, there are several SGLT2 inhibitors on the market that include 61 (dapagliflozin), 63 (canagliflozin), 64 (ipragliflozin), 65 (empagliflozin), and 67 (luseogliflozin) for T2DM (Figure 21). Here we will focus on these drugs and their potential impact in NAFLD and NASH.

Figure 21

Figure 21. Structures of SGLT inhibitors (59, 61, 6365, 67) with their reported IC50 or EC50 values against SGLT1 and SGLT2 in vitro. Initial starting points (60, 62, 66) for the optimization of these inhibitors are also shown.

Compound 63 (Figure 21), developed by the Mitsubishi Tanabe Pharma Corporation and later marketed by JNJ, was the first SGLT2 inhibitor approved (in 2011 by the European Union). Key to the discovery of 63 was to develop a compound with selectivity for SGLT2 over SGLT1. Previously, O-glucosides had been identified by researchers at Tanabe Seiyaku Co. as selective and potent SGLT2 inhibitors.(267) One issue that was observed with O-glucosides, however, was their metabolic instability. Novel C-glucosides were therefore being explored as metabolically more stable than the O-glucosides, including C-glucoside 62 (Figure 21) from BMS.(268) Building off this discovery, the Mitsubishi Tanabe Pharma Corporation team explored SAR focused on substituting the phenyl ring linked to the sugar moiety with various heteroaromatic rings, and compound 63 was identified.(269) This compound showed good oral bioavailability (85%) in rats, and oral administration at 30 mg/kg to male rats increased glucose excretion over 24 h by 3696 mg per 200 g of body weight compared to vehicle treated rats. Several recent clinical trials in Japan have evaluated compound 63 in NAFLD and NASH patients. In one study, nine patients with NAFLD and T2DM were given 63 (100 mg once daily) for 24 weeks, and liver histology was evaluated.(270) All nine patients achieved histological improvement compared to baseline. At 24 weeks, steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33%, respectively, compared to the pretreatment. In another trial, thirty-five patients with NAFLD were enrolled and administered 63 (100 mg).(271) Body weight and serum levels of AST, ALT, and triglycerides decreased significantly after 3 and 6 months of 63 treatment compared to baseline. Lastly, one clinical study enrolled T2DM patients with NASH (hepatic fibrosis stage 1–3 confirmed by liver biopsy) and administered 63 (100 mg) once a day for 12 weeks.(272) There was a significant decrease in ALT levels in the treated patients at week 12 compared to baseline (mean −23.9 U/L). Significant improvements in hepatic function and fibrosis markers, such as AST, fibrosis-4 index, and body weight were also found.
Compound 61 (Figure 21), also a C-glucoside, was discovered and developed at BMS using O-glucoside 60 (Kissei Pharmaceutical Co.; Figure 21) as a starting point.(273,274) SAR exploration of the C-aryl glucosides revealed that meta-substituted diarylmethanes were more potent than the biphenyl counterpart. Building on this observation, compounds with C-4′ and C-4 substitutions were evaluated and culminated in the discovery of 61, a potent and selective SGLT2 inhibitor with increased stability. Several clinical trials have evaluated 61 as a potential treatment for NAFLD and NASH. In one study, patients with abnormal ALT levels were divided into two groups, receiving either metformin + 61 or metformin + DPP4 inhibitors (DPP4i).(275) The cohort receiving compound 61 showed more pronounced weight loss and larger ALT decline compared to the patients receiving DPP4i; the proportion of patients with ALT normalization after treatment was also significantly higher in the 61-dosed group. In addition, 61 was assessed for safety and efficacy in a single-arm, nonrandomized, open-label study for the treatment of NASH associated with T2DM.(276) Patients with liver biopsy-confirmed NASH and T2DM were enrolled and administered 61 (5 mg/day) for 24 weeks. Treatment with 61 was associated with significant decreases in body mass index compared to baseline with changes driven by reductions in body fat mass and percent body fat. AST and ALT levels also significantly decreased during the study compared to pretreatment levels. Finally, a randomized, active-controlled, open-label trial of 61 was conducted in patients with T2DM and NAFLD (n = 57). Patients were randomized to receive 61 (5 mg/day) or placebo and were treated for 24 weeks. For the 61-treated group, there was a significant improvement in liver fibrosis, ALT levels, and visceral fat mass.(277) A phase 3 trial is currently underway that will assess the efficacy and safety of 61 on improving NASH as determined by liver biopsies and metabolic risk factors. The primary outcome measure will be improvement in scored liver histology over 12 months.
Compound 64 (Figure 21), approved for use in the US in 2014, was identified by Boehringer Ingelheim and developed in partnership with Lilly as a treatment for T2DM.(278) Several clinical studies have evaluated the effectiveness of 64 for NAFLD and NASH. A phase 4 single-arm, open-label, pilot study enrolled nine biopsy-proven NASH patients with T2DM who were given 64 (25 mg daily) for 24 weeks (ClinicalTrials.gov identifier NCT02964715).(279) This study found a significant reduction in body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, volumetric liver fat fraction, steatosis, ballooning, and fibrosis compared to baseline measurements. In another clinical study, 50 patients with T2DM and NAFLD were randomized to receive 64 or placebo for 20 weeks (ClinicalTrials.gov identifier NCT02686476).(280) Compound 64 treatment significantly reduced liver fat (as measured by MRI-PDFF) and improved ALT levels.
Benzothiophene 65 (Astellas Pharma; Figure 21) was also derived from C-glucoside 62 and was approved in 2014 for the treatment of T2DM in Japan.(281) Here, the strategy was to replace the phenyl rings with heteroaromatics. While replacement of the internal phenyl ring was not productive, replacement of the distal phenyl ring with a benzothiophene and addition of a fluorine to the internal phenyl of 62 led to the identification of 65, a potent and selective SGLT2 inhibitor. Researchers at Astellas showed that 65 prevented hepatic triglyceride accumulation and fibrosis in choline-deficient l-amino acid defined diet fed rats. A phase 4 study investigated 65 for its potential to reduce visceral fat area and fatty liver in subjects with T2DM when added to metformin and pioglitazone therapy (ClinicalTrials.gov identifier NCT02875821), but results have not yet been published.
Compound 67 (Figure 21) was identified and developed by Taisho Pharmaceutical and approved in Japan in 2014.(282) For the compounds discussed so far, structural modifications have primarily occurred on the aryl alkyl side of the molecule. Researchers at Taisho Pharmaceutical focused on the glycoside, where they substituted the glucose oxygen with sulfur in order to hinder degradation. Initial compounds, such as 66 (Figure 21), were shown to increase urinary glucose excretion and lower blood glucose in rats. In order to achieve a lower in vivo dose, the researchers focused on developing a more metabolically robust and effective compound. Keeping the thioglycoside in place, the SAR focused on the aryl alkyl linker to arrive at compound 67, which was stable in human liver microsomes and hepatocytes. Compound 67 had good oral bioavailability and favorable PK in dogs. Oral administration of 67 (1 mg/kg) in dogs resulted in a dramatic enhancement of urinary glucose levels (>2600-fold). Compound 67 has subsequently been tested for its impact on liver outcomes in several clinical studies. In one study in Japan, T2DM patients were randomized to receive 67 or metformin.(283) The study showed that 67 significantly reduced liver fat deposition compared to metformin, as measured by liver-to-spleen attenuation ratio (obtained by CT) at 6 months compared to baseline. In another trial, T2DM patients with NAFLD were treated with 67 (2.5 mg/day) for 24 weeks.(284) HbA1c levels and hepatic steatosis were evaluated by MRI-PDFF and compared to baseline; both significantly decreased following therapy, with the reduction of hepatic fat correlated with reduced levels of ALT.

Stearoyl Coenzyme A Desaturase 1

Stearoyl-coenzyme A desaturase 1 (SCD1) is an integral membrane enzyme that catalyzes the rate-limiting step in the synthesis of monounsaturated fatty acids. SCD1 is a key enzyme that modulates fatty acid metabolism in the liver and therefore an interesting target for NASH.(285,286) SCD1 knockout mice show a decrease in fatty acid synthesis and increase of fatty acid β-oxidation, resulting in decreased hepatic storage of triglycerides.(287) In addition, SCD1 deficiency has been demonstrated to prevent hepatic steatosis in a mouse model of NAFLD.(288)
Compound 68 (aramchol; Figure 22) is a SCD1 inhibitor being developed by Galmed. In a mouse model of NASH, 68 treatment was shown to improve steatohepatitis and fibrosis.(285) In a phase 2 clinical trial, 68 treatment reduced liver fat content in a dose-dependent manner in patients with NAFLD or NASH (ClinicalTrials.gov identifier NCT01094158).(286) Recently, one-year results were disclosed for a phase 2b randomized placebo-controlled trial of 68 (ARREST, ClinicalTrials.gov identifier NCT02279524).(289) Compared to placebo, patients treated with 68 at 600 mg had higher rates of NASH resolution without worsening of fibrosis, fibrosis stage reduction without worsening of NASH, and decreases in ALT and AST. Currently, a phase 3 study is planned that will evaluate the efficacy and safety of 68 versus placebo in subjects with NASH (ARMOR; ClinicalTrials.gov identifier NCT04104321). This is a 52-week study with a completion date in 2024.

Figure 22

Figure 22. SCD1 inhibitor (68).

Inflammation Targets

ARTICLE SECTIONS
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Apoptosis Signal-Regulating Kinase 1

Apoptosis signal-regulating kinase 1 (ASK1) is a serine/threonine protein kinase in the mitogen-activated protein kinase kinase kinase (MAP3K) enzyme family and acts upstream of Jun N-terminal kinase (JNK) and p38.(290) ASK1 is activated by various factors, such as tumor necrosis factor α (TNFα), lipopolysaccharide, endoplasmic reticulum stress, calcium influx, and oxidative stresses including reactive oxygen species.(291−293) Under nonstress conditions, ASK1 dimerizes and is negatively regulated by binding of its N-terminal noncatalytic region to thioredoxin (TRX), a reduction/oxidation regulatory protein. Reactive oxygen species induce the oxidized form of TRX, and as a result, TRX dissociates from ASK1 and the kinase is activated. ASK1 then phosphorylates and activates an intermediate kinase (MAPK kinase 4), which in turn activates the JNK and p38 pathways in hepatic cells. These pathways lead to apoptosis, inflammation, and fibrosis.
ASK1 inhibitors(294−297) have historically been developed for various indications, but none were advanced to the clinic. Recently, there has been renewed interest in testing ASK1 inhibitors as a treatment for NASH, either as a standalone therapy or in combination with other liver antisteatotic drugs. Studies with rodent models have supported the potential utility for ASK1 inhibitors as a treatment for NASH.(298) The most advanced ASK1 inhibitor in clinical development is compound 72 (Gilead, selonsertib, GS-4997; Figure 23).(299,300)

Figure 23

Figure 23. Evolution of ASK1 inhibitor 72 with reported IC50 and EC50 values.

Compound 72 was discovered through structure-based drug design from a moderately active high throughput screening hit 69 (Figure 23).(301) In this scaffold, the amide carbonyl oxygen serves as the hinge binder with Val757 and the triazole nitrogen maintains a crucial polar interaction with catalytic residue Lys702, as shown in the cocrystal structure with the ASK1 kinase domain (Figure 24A). One interesting aspect of ASK1 is that it exists as a homodimer in a head-to-tail arrangement. Compound 70 (Figure 23) improved upon the potency of 69 by filling a hydrophobic pocket near the triazole N-methyl, and the pyridine nitrogen interacts with Tyr814 in the adjacent dimer protein (Figure 24B). Compound 71 (Figure 23) maintains similar interactions as observed with 70, but now the imidazole nitrogen forms a cross dimer hydrogen bond with Tyr814 (Figure 24C). Additionally, the two cyclopropyl groups near the dimer interact favorably and have a distance of 3.3 Å from each other. Further SAR on the pyridine ring of 71 led to 72.

Figure 24

Figure 24. Crystal structures of compounds (A) 69, (B) 70, and (C) 71 with ASK1 (PDB 6E2M, 6E2N, and 6E2O, respectively).

Compound 72 has been advanced in multiple NASH clinical trials. A randomized phase 2 trial in 72 patients tested the safety and efficacy of 72 (6 mg or 18 mg orally QD) alone or in combination with the lysyl oxidase-like 2 antibody simtuzumab (SIM; 25 mg SC weekly) in NASH patients with fibrosis (ClinicalTrials.gov identifier NCT02466516).(302) While SIM did not show efficacy in this trial, compound 72 at either dose level with or without SIM showed marked reductions in fibrosis and likelihood of progression to cirrhosis, as well as reduced liver stiffness (by MRE) and liver fat (by MRI-PDFF) compared to SIM alone. Patients treated with 72 showed a dose-dependent response rate of fibrosis improvement ≥1 stage from baseline (43% at 18 mg dose and 30% at 6 mg dose) and reduced rate of progression to cirrhosis (3% at 18 mg dose and 7% at 6 mg dose). Both fibrosis improvement and progression to cirrhosis were seen in 20% of patients receiving placebo.
Following this phase 2 trial, Gilead initiated two 48-week phase 3 trials of 72 in patients with NASH. STELLAR-3 (ClinicalTrials.gov identifier NCT03053050) studied 72 in 802 patients with bridging fibrosis (stage F3), while STELLAR-4 (ClinicalTrials.gov identifier NCT03053063) enrolled 877 patients with compensated cirrhosis (F4) due to NASH. Unfortunately, neither trial met the pre-specified primary endpoint of ≥1 stage histologic improvement in fibrosis without worsening of NASH. In addition, topline results for a phase 2 clinical trial evaluating the combination of 72 with FXR agonist 12 and ACC inhibitor 37 were recently reported (ATLAS; ClinicalTrials.gov identifier NCT03449446).(303,304) ATLAS is a 48-week, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of all three drugs and combinations in subjects with bridging (F3) fibrosis or compensated cirrhosis (F4) due to NASH. No combination regimen (12, 30 mg; 37, 20 mg; 72, 18 mg) led to a statistically significant increase in the proportion of patients who achieved the primary efficacy end point of a ≥1-stage improvement in fibrosis without worsening of NASH. There was a statistically significant improvement in the markers of fibrosis and liver function with patients treated with a combination of 37 and 12 compared with placebo in patients with advanced fibrosis.

Caspase

Caspases are a family of protease enzymes that mediate programmed cell death (e.g., apoptosis, necroptosis), as well as inflammatory and immune responses.(305) Once activated, caspases recognize and cleave substrates at specific aspartic acid residues, degrading key proteins that are essential for cell viability.(306,307) Because apoptosis is a highly regulated process that helps eliminate defective cells to maintain tissue homeostasis, any disruption to this process can lead to tissue damage and loss of function.(308) Dysregulation of caspases is involved in disease states such as neurodegenerative disorders, stroke, chronic inflammation, and cancer. Caspases are also thought to be involved in the production of hepatic microvesicles that lead to the activation of profibrotic gene expression.(309) Additionally, caspase family members have been shown to play an important role in activating the inflammasome.(305) Several caspase inhibitors have advanced to the clinic for the treatment of diseases such as rheumatoid arthritis, psoriasis, and liver impairment from hepatitis C virus.(310)
Compound 74 (emricasan; Figure 25) was identified by Idun Pharmaceuticals and was being developed by Conatus Pharmaceuticals and Novartis for the treatment of liver disease.(311,312) Previous work identifying pan-caspase inhibitors resulted in compounds with the general structure of 73 (Figure 25).(313) Substitutions on the R group resulted in compounds with low micromolar potency in an anti-Fas antibody-stimulated Jurkat E6.1 cell lymphoma cell line (JFas). Further SAR around the P4 oxamide and warhead moiety of 73 resulted in the identification of 74. In mice, treatment with 74 significantly attenuated hepatocyte apoptosis and caspase-3 and -8 activities that had been induced by a high fat diet. AST, ALT, and NAS were also decreased in 74-treated rodents, indicating a reduction in liver injury and inflammation.(314) Recently, results were released for a phase 2b clinical trial evaluating 74 (5 mg and 50 mg) in patients with NASH fibrosis (ENCORE-NF; ClinicalTrials.gov identifier NCT02686762).(315) Unfortunately, 74 failed to meet the primary end point of one point or greater improvement in fibrosis stage without worsening of steatohepatitis. After 72 weeks of treatment, patients who received 74 had response rates of 11.2% (5 mg dose) and 12.3% (50 mg), while patients receiving placebo had a significantly better response rate (19%). There were, however, statistically significant reductions in ALT levels in the 74-treated group compared to placebo. Results for another phase 2 study of 74 in patients with NASH cirrhosis were also recently announced (ENCORE-LF; ClinicalTrials.gov identifier NCT03205345) and did not meet the primary end point of event-free survival (defined as a composite of all-cause mortality, new decompensation events, or ≥4 points progression in model for end-stage liver disease [MELD] score).(316) There were no significant differences in event rates between the 74-treated and placebo arms and no clear trends indicating a potential treatment effect. In October 2019, both Conatus and Novartis announced that they will terminate their agreement, and it appears that 74 is no longer being investigated for the treatment of NASH.(312)

Figure 25

Figure 25. Caspase inhibitor 74 and precursor 73.

Chemokine Receptors

Chemokine receptors (CCR) are G-protein coupled receptors that, upon ligand binding, trigger a downstream cascade central to controlling basal and inflammatory leukocyte trafficking.(317) Chemokine receptors have emerged as potentially important factors in various liver diseases, and both chemokine receptor 2 (CCR2) and chemokine receptor 5 (CCR5) have been implicated in the progression of NASH and fibrosis. It was shown in mice that overexpression of CCR2 ligand, chemokine ligand 2 (CCL2), leads to adipose tissue inflammation and hepatic steatosis.(318) Additionally, deletion of CCR2 in mice was found to attenuate obesity and decrease recruitment of macrophages in adipose tissue.(319) CCR5 has also been reported to have high expression levels in adipose tissue associated with genetic or diet-induced obesity.(320) In CCR5-deficient mice, protection from insulin resistance and hepatic fat infiltration was observed. Both CCR2 and CCR5 appear to also play a role in hepatic fibrogenesis, as deletion of these genes significantly protected from liver fibrosis.(321−323) CCR5 is also a primary co-receptor for HIV infection.
Compound 76 (cenicriviroc; Figure 26), a dual CCR2/CCR5 antagonist, is currently in clinical trials for the treatment of NASH and liver fibrosis. Compound 76 was originally pursued by Takeda as a treatment for HIV infection. Early work at Takeda identified 75 (Figure 26) as an anti-HIV-1 candidate for injection, but with poor oral availability.(324) With the goal of developing an orally available clinical candidate, the researchers investigated the quaternary ammonium moiety as a possible impediment to exposure. Replacement of this group with [6,7]-fused 1-benzoxepine, 1-benzthiepine-1,1-dioxide, or 1-benzazepine compounds containing a tertiary amine, pyridine N-oxide, or sulfoxide moieties led to the discovery of potent, orally bioavailable compounds.(325−327) Further SAR on a sulfoxide series led to 76, which entered clinical trials for the treatment of HIV.(328) Subsequently, Tobira Therapeutics acquired 76 and pursued its development for liver diseases; in 2016, Allergan gained rights to 76 with their purchase of Tobira. Compound 76 has been widely studied in preclinical models of liver disease.(329) In a mouse model of NASH and rat model of liver fibrosis, 76 lowered ALT levels, reduced collagen deposition in the liver, and improved NAS.(330) A phase 2 study evaluated 76 for efficacy and safety in NASH patients with liver fibrosis (CENTAUR; ClinicalTrials.gov identifier NCT02217475).(331,332) The primary end point of NAS improvement and resolution of steatohepatitis was seen in similar proportion in the treatment and placebo groups. However, the improvement in fibrosis end point (based on liver biopsy) was met in significantly more subjects on 76 than placebo. With these data in hand, a phase 3 study with 76 is currently recruiting and will examine the end point of improvement in fibrosis of at least 1 stage and no worsening of steatohepatitis at 1 year (AURORA; ClinicalTrials.gov identifier NCT03028740). In addition, patients will be evaluated for long-term clinical outcomes, including histopathologic progression to cirrhosis and liver-related clinical outcomes. Lastly, a phase 2 trial is currently recruiting that will evaluate the combination of FXR agonist 13 and 76 in patients with NASH and liver fibrosis (ClinicalTrials.gov identifier NCT03517540).

Figure 26

Figure 26. CCR2/5 antagonist 76 and its precursor 75. IC50 values for CCR2 and CCR5 binding are shown.

Mineralocorticoid Receptor

The mineralocorticoid receptor (MR) is a nuclear receptor expressed in many tissues, including the kidney, colon, heart, hippocampus, brown adipose tissue, and liver.(333) The receptor, which is activated by aldosterone and glucocorticoids, is involved in the modulation of ion and fluid transport for osmotic and hemodynamic homeostasis, membrane excitability in neurons and muscle cells, and neuronal responses essential for learning, memory, and response to stress. The MR ligand aldosterone induces inflammation by stimulating the formation of reactive oxygen species and also promotes the production of collagen.(334−336) Antagonism of the MR has been shown to reduce collagen levels in a rodent study.(337) In a transgenic mouse model, 77 (eplerenone; Figure 27),(338) an MR antagonist approved for management of chronic heart failure and high blood pressure, was shown to reduce inflammation in adipose tissue, reduce steatohepatitis, and reduce hepatic fibrosis.(339) Another preclinical study involved mice fed a choline-deficient-amino-acid diet and found that animals treated with compound 77 had reduced liver steatosis and fibrosis.(340)

Figure 27

Figure 27. MR antagonists (77 and 78)

To date, only one MR antagonist, 78 (apararenone, MT-3995; Figure 27), has progressed into clinical trials for NASH (ClinicalTrials.gov identifier NCT02923154).(341) Compound 78 is a nonsteroidal MR antagonist being developed by Mitsubishi Tanabe. No preclinical data have been disclosed, and the compound is now being evaluated in a phase 2 study of NASH patients with a primary end point of change from baseline in ALT.

Vascular Adhesion Protein-1

Vascular adhesion protein-1 (VAP-1, also known as amine oxidase containing copper, AOC3) is a glycosylated homodimeric membrane protein that plays several roles in inflammation. As a copper-dependent amine oxidase within the semicarbazide-sensitive amine oxidase (SSAO) enzyme family, VAP-1 breaks down short-chain primary amines (e.g., benzylamide and methylamine) to produce aldehyde, ammonium, and hydrogen peroxide. In addition to its enzymatic activity, VAP-1 also functions as an adhesion molecule to facilitate binding and migration of leukocytes through the endothelium. VAP-1 is highly expressed in cells of the endothelium, smooth muscle, and adipose tissue.(342−344) Under normal conditions, VAP-1 is stored within intracellular vesicles and rapidly translocates to the cellular surface in response to inflammatory signals.(343) A soluble form of VAP-1 (sVAP-1) is generated by proteolytic cleavage of membrane-bound VAP-1 by metalloproteases, a process enhanced by inflammatory cytokines including TNFα.(345) sVAP-1 is an important source of damaging systemic reactive oxygen species and advanced glycation end products, likely through the production of hydrogen peroxide and formaldehyde, respectively.(346)
Elevated sVAP-1 levels have been implicated in numerous diseases, including cancer, cardiovascular, inflammatory, and metabolic syndromes, as well as liver disease.(347,348) In NASH patients, sVAP-1 levels are significantly correlated with disease severity and predictive of fibrosis.(349) In multiple animal models of NASH, VAP-1 deficient mice (Aoc3–/–) showed significantly less fibrosis, inflammation, and leukocyte infiltration into the liver. Similar results were observed using a VAP-1-specific monoclonal antibody.(349) Taken together these data suggest that VAP-1 is not simply a marker of liver injury, but a key mediator of the damaging inflammatory state that defines NASH disease.
While a number of small molecule inhibitors of SSAO enzymes have been discovered,(350) only two compounds are being pursued as a potential treatment in NASH. Compound 82 (PXS-4728A, BI-1467335; Figure 28) discovered by Pharmaxis, is the most advanced VAP-1 inhibitor and has been extensively profiled in vivo.(351) To identify 82, researchers at Pharmaxis began with a known monoamine oxidase B (MAO-B) inhibitor, compound 79 (mofegiline; Figure 28), which had progressed to phase 2 clinical trials for the treatment of Parkinson’s disease.(352) Although selective for MAO-B versus MAO-A, 79 was also found to potently inhibit VAP-1. Mechanistically, 79 is believed to be recognized as a substrate for VAP-1 where it covalently attaches to the enzyme via the haloallylamine. Further efforts at Pharmaxis sought to identify VAP-1 selective inhibitors. Upon analysis of the binding pocket of VAP-1, the researchers noted that the fluorophenyl could be redesigned to better fill the pocket. Subsequent SAR in this area resulted in the identification of 80 (Figure 28), which was potent and selective for VAP-1 over MAO-A and MAO-B.(353) To further optimize selectivity, PK, and cross-species potency, SAR was explored on the phenyl ring and 81 and 82 were identified (Figure 28).(351,354) In a cholesterol-fed rabbit model of atherosclerosis, treatment with compound 82 lowered plasma lipid levels, reduced expression of adhesion molecules and inflammatory cytokines, and suppressed recruitment and activation of macrophages at the sites of atherosclerotic lesions.(355,356) In models of acute lung disease, 82 treatment reduced lipopolysaccharide (LPS)-induced neutrophil lung migration and cytokine-induced cell migration by diminishing leukocyte rolling and adherence.(351) Similarly, in models of acute and chronic cigarette smoke-induced lung disease, 82 treatment suppressed airway infiltration of inflammatory immune cells, reduced pulmonary fibrosis, and improved lung function.(357) Compound 82 was acquired by Boehringer Ingelheim in 2015 and a year later obtained FDA Fast Track Designation for development in the treatment of NASH. In June 2017, Boehringer initiated a 12-week, placebo-controlled, phase 2a multiple dose study to investigate the safety and efficacy of 82 in 114 patients with clinical evidence of NASH (ClinicalTrials.gov identifier NCT03166735). The study met the targets for inhibition of plasma VAP-1 activity by 82 compared to placebo, as well as clinically relevant changes in NASH biomarkers. In December 2019, Boehringer Ingelheim announced the discontinuation of the development of 82 in NASH based on the risk of drug interactions of the compound in these patients.(358)

Figure 28

Figure 28. VAP-1 inhibitors (7982) and their reported IC50 values for VAP-1, MAO-A, and MAO-B.

The second VAP-1 inhibitor being developed for NASH is TERN-201. TERN-201 is a potent, highly selective irreversible VAP-1 inhibitor that was originally discovered by Eli Lilly and is currently being developed by Terns Pharmaceuticals. In a phase 1 study, TERN-201 was generally well tolerated and showed inhibition of SSAO activity after a single dose in healthy volunteers.(359)

Fibrosis Targets

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Lysyl Oxidase-like 2

The lysyl oxidases are a family of secreted enzymes involved in remodeling the extracellular matrix.(360,361) Specifically, these enzymes catalyze the copper-dependent oxidative deamination of the terminal ε-amine of lysine and hydroxylysine residues in collagen and elastin to generate the aldehyde allysine. Further reaction with neighboring allysines and lysines leads to covalent cross-linking in the extracellular matrix.(362) While this is a normal part of tissue remodeling, imbalance in this process can lead to excessive cross-linking and impaired organ function.(363−366) This aberrant cross-linking often leads to fibrosis, which is characterized by scarring and tissue stiffness and if left untreated will lead to organ failure. NASH patients with advanced fibrosis are only a small subset of the overall population, but fibrosis progression is generally accelerated in NASH,(367) putting patients at higher risk of developing severe liver disease. Lysyl oxidase-like 2 (LOXL2) is one member of the lysyl oxidase family that has been shown to be upregulated in fibrotic tissue and implicated in the progression of various diseases.(368−370) This enzyme has therefore become an interesting target for fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF),(371) and a potential target to reduce fibrosis associated with NASH.(372)
A potent LOXL2 monoclonal antibody (simtuzumab; SIM) has been developed but, unfortunately, did not show promise in phase 2 clinical trials. Two separate phase 2 studies were stopped prematurely after 96 weeks of treatment due to lack of efficacy in patients with bridging fibrosis or compensated cirrhosis caused by NASH (ClinicalTrials.gov identifiers NCT01672866 and NCT01672879).(373) In one study, all three dose groups of patients with bridging fibrosis had a decrease in hepatic collagen, but there was no difference between SIM-treated patients and those receiving the placebo. In addition, SIM did not significantly decrease fibrosis stage or liver-related clinical events in patients with cirrhosis. Another phase 2 trial evaluated SIM in patients with primary sclerosing cholangitis (ClinicalTrials.gov identifier NCT01672853).(374) Again, SIM did not lead to significant reductions in fibrosis stage, progression to cirrhosis, or frequency of clinical events compared to placebo. The disappointing results of these clinical trials are in stark contrast to preclinical studies with SIM, where it was shown to be effective in liver fibrosis models.(370) The clinical results have called into question the potential utility of antibody-based LOXL2 inhibitors.
Recognizing the failure of SIM, researchers from PharmAkea proposed that a small molecule should have significant advantages over an antibody.(370) A small molecule can bind directly to the enzyme active site to maximize inhibition, as well as more easily permeate the fibrotic matrix and intracellular compartments. One goal of these researchers was to identify inhibitors of LOXL2 that are selective over the related family member LOX, since LOX-deficient mice have severe cardiovascular and pulmonary defects.(375,376) A screening campaign identified 83 (Figure 29) as having 30-fold selectivity for LOXL2 over LOX. After replacing the 2-chloro with various substituted O-phenyl rings and substitution of the pyridine ring with a trifluoromethyl group, 84 (PAT-1251; Figure 29) was identified as having improved whole blood potency compared to 83. Analogues of 84 were shown to be irreversible inhibitors and hypothesized to form a tight Schiff base complex with the enzyme. Further evaluation of 84 in a mouse bleomycin lung fibrosis model showed significant reduction in disease. Interestingly, PharmAkea has posted data on their Web site indicating the antibody AB0023 (mouse version of SIM) does not bind to the catalytic domain or inhibit the oxidative activity of LOXL2 while 84 directly inhibits the enzyme.(377) Further data posted by PharmAkea reports that 84 significantly reduces liver fibrosis in a preclinical model, outperforming AB0023. A phase 1 clinical trial has completed that evaluated single and multiple dose safety, tolerability, PK, and food effect of 84; results have not been reported (ClinicalTrials.gov identifier NCT02852551).

Figure 29

Figure 29. LOXL2 inhibitors (83, 84, and 86) with reported IC50 values in cell culture media (CCM) and whole blood (hWB) and LOX IC50 values.

PXS-5153A is another small molecule LOXL2 inhibitor being developed by Pharmaxis for treatment of NASH and IPF.(378) The structure of PXS-5153A has not been disclosed, but a recent publication reported 86 (PXS-5120A; Figure 29), a potent and selective LOXL2 inhibitor. The ethyl ester prodrug of 86, compound 85 (Figure 29), displayed antifibrotic activity in mouse models of liver and lung fibrosis.(379) PXS-5153A is a dual LOXL2/LOXL3 inhibitor that was specifically designed to interact with the lysine tyrosylquinone (LTQ) cofactor in the LOXL2/LOXL3 catalytic pocket and, upon elimination of the fluoride-leaving group, forms a covalently bound enzyme–inhibitor complex. PXS-5153A was shown to be efficacious in a carbon tetrachloride (CCl4)-induced liver fibrosis rodent model, where compound treatment significantly reduced hydroxyproline (a marker of a collagen content) and liver injury compared to vehicle. In a STAM mouse model, which is considered to be representative of NASH, PXS-5153A treatment significantly reduced hepatocyte ballooning and NAS.(380) In addition, hydroxyproline was reduced in the treated group compared to control. Two phase 1 clinical trials have been completed with two different compounds according to the Pharmaxis Web site;(381) results have not been reported.

Galectin 3

Galectins are a large family (15 members) of soluble proteins that bind specifically to β-galactoside sugars.(382,383) These proteins have been implicated in many biological processes, including the modulation of various transmembrane signaling pathways, mediation of cell–cell interactions, regulation of RNA splicing, and cell-matrix adhesion. Galectins form noncovalent homodimers in solution via a carbohydrate recognition domain (CRD) or may have two distinct CRDs at their N- and C-termini; galectin 3 (Gal-3) is the only member that has a CRD at the C-terminus and a nonlectin peptide motif at the N-terminus.(384) Gal-3 has been implicated in the pathogenesis of liver fibrosis, as its expression is increased in fibrotic tissue from patient liver biopsies.(385) In addition, Gal-3 null mice are resistant to liver fibrosis in mouse models of NASH.(386,387)
Galectin Therapeutics is developing GR-MD-02, a galactoarabino-rhamnogalacturonan polysaccharide polymer consisting of galacturonic acid, galactose, arabinose, rhamnose, and smaller amounts of other sugars. GR-MD-02 binds to Gal-1 (Kd = 10 μM) and Gal-3 (Kd = 8 μM), thereby preventing inflammation and fibrosis-associated effects.(384) In a phase 2b study, GM-MD-02 was evaluated in patients with NASH cirrhosis and portal hypertension. Unfortunately, the compound did not improve hepatic venous pressure gradient (HVPG) or liver fibrosis in the total study population; ballooning significantly improved at the 2 mg/kg dose but did not improve at 8 mg/kg (ClinicalTrials.gov identifier NCT02462967).(388) There did, however, appear to be a clinical benefit of GR-MD-02 in the subsets of NASH patients with cirrhosis without esophageal varices (a marker of poor blood flow to the liver) or with mild pulmonary hypertension. At the 2 mg/kg dose, GR-MD-02 significantly decreased HVPG in these subsets (43% of patients receiving GR-MD-02 had ≥2 mmHg decrease vs 13% of patients on placebo), although the 8 mg/kg dose again did not show significant effects; no explanation has been disclosed for this observation. Galectin Therapeutics has announced that a phase 3 clinical study of GR-MD-02 will proceed in patients with NASH cirrhosis without esophageal varices. The primary end point will be either change in HVPG or the progression to esophageal varices.(389)

Summary and Outlook

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NASH is a serious and increasingly common liver disease that is projected to overtake viral hepatitis as the leading indicator for liver transplantation. NASH patients are at higher risk of developing severe liver disease, including cirrhosis and hepatocellular carcinoma. NASH also significantly increases the risk of developing cardiovascular disease, the leading cause of death in this patient population. NASH is strongly associated with T2DM and obesity and is generally considered the liver manifestation of metabolic syndrome. The goal of NASH therapy is to improve the necro-inflammatory state of the liver and ultimately halt, or ideally reverse, the development and progression of fibrosis. Although lifestyle changes including weight loss have shown benefit, sustaining these changes in the long term is challenging, and therapeutic interventions are clearly needed. Currently, however, there are no approved drugs for the treatment of NASH.
Several factors have contributed to the challenge of NASH drug development. NASH is a complicated disease (highly heterogeneous patient population with comorbidities), with some predisposed patients developing the disease, while others with significant risk factors may not. Diagnostic criteria are an aggregate of histological attributes from liver biopsy, which can lead, for example, to patients being diagnosed with the same severity of NASH despite potentially meaningful differences in the component histological features. It is therefore likely that not every patient progresses to NASH for the same reasons or in the same way. As a result, individual patients may respond very differently to the same therapeutic intervention, despite ostensibly similar clinical diagnoses. Further contributing to the difficulties of NASH drug development are the very long treatment durations (>1 year) that have been needed in clinical trials to achieve NASH resolution, as well as the requirement for liver biopsy to monitor this effect. Finally, NASH drug development has been hindered by the lack of reliable, translatable animal models to study the disease and test new therapies. The most commonly used mouse models only recapitulate certain aspects of NASH and generally cannot be used to accurately predict therapeutic response in the clinic.(390) More sophisticated mouse models that more closely resemble the human disease and include pre- and post-treatment liver biopsy have been described but require specialized animal handling and are not widely available.(391)
In spite of these challenges, the NASH drug development landscape is relatively large and diverse, with over 20 unique targets across metabolism, inflammation, and fibrosis being pursued. Compound 7 (FXR agonist; Figure 3) being developed by Intercept is the most advanced drug candidate. Compound 7 showed positive data in a phase 3 study in NASH patients (REGENERATE; ClinicalTrials.gov identifier NCT02548351) and is approved for use in patients with primary biliary cholangitis. Compound 4 (PPAR-α/δ agonist; Figure 2) being developed by Genfit is the next most advanced compound and interim results from its pivotal phase 3 study are expected in early 2020 (RESOLVE-IT; ClinicalTrials.gov identifier NCT02704403). Compound 72 (ASK1 inhibitor; Figure 23) being developed by Gilead recently completed two phase 3 studies (STELLAR-3 [ClinicalTrials.gov identifier NCT03053050] and STELLAR-4 [ClinicalTrials.gov identifier NCT03053063]). Unfortunately, 72 did not show statistically significant improvements in either NASH or fibrosis in these studies, despite showing therapeutic benefit in an earlier open label phase 2 study (ClinicalTrials.gov identifier NCT02466516).(302) The results with 72 highlight the uncertainty of extrapolating positive phase 2 data to phase 3 studies, which may be especially difficult for NASH due to disease diversity in larger populations. While 4 and 7 are currently in the lead to reach market, several drugs continue to show great promise in phase 2 studies, with robust pharmacological effects in NASH patients. For example, 20 (THR-β agonist; Figure 7) being developed by Madrigal showed profound reductions in liver steatosis, along with statistically significant improvements in NASH (ClinicalTrials.gov identifier NCT02912260). Additionally, drugs already approved for other indications, including T2DM and obesity (e.g., GLP-1R agonists), are now entering NASH clinical trials either alone or in combination with other candidates (ClinicalTrials.gov identifiers NCT02970942 and NCT03987074).
As frontrunner compounds enter the clinic, additional exciting advances are being made that were beyond the scope of this review. For example, the concept of unimolecular coagonists is emerging, with the most advanced being GLP-1R agonists(392) that also show activity against other receptors, including gastric inhibitor polypeptide receptor (GIPR), glucagon receptor (GCGR), and most recently, FGF21.(393) Another emerging target is soluble guanylate cyclase (sGC), an enzyme involved in nitric oxide (NO) sensing. Praliciguat, a NO-dependent activator of sGC being developed by Cyclerion, reduced fibrosis and the expression of inflammatory genes in preclinical models of NASH.(394) Integrins (particularly subtypes αvβ6 and αvβ1) have also generated interest as novel targets for NASH and fibrosis, after previously being pursued by the pharmaceutical industry for indications such as cancer and psoriasis.(395) Recently, Morphic Therapeutic and Pliant Therapeutics have both partnered their programs on integrin inhibitors.(396−398) Pliant’s partnership with Novartis will aim to develop preclinical asset PLN-1474, an inhibitor of integrin αvβ1, for the treatment of liver fibrosis associated with NASH.(396)
While a large and diverse pipeline of potential NASH therapies is racing toward the market, the first approved drugs will not end the race. Combinations of treatments will almost certainly be necessary to address the multiple pathologies associated with NASH. Even single agents that can impact multiple pathways (e.g., FXR or PPAR agonists) will likely achieve greater benefit when combined with other agents that increase impact on one or more targets. For example, a FXR agonist, which can improve metabolic function and reduce inflammation and fibrosis, could benefit from being combined with a drug that can profoundly reduce liver fat (e.g., THR-β agonist). Given the lack of translatable animal models, optimal drug combinations will need to be determined in the clinic, and several phase 2 combination studies are currently ongoing (Table 2). Results from these early combination trials will be the most highly anticipated and most significant development for treatment of NASH.

Author Information

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  • Corresponding Authors
  • Authors
    • Yingzi Xu - Terns Pharmaceuticals, 1065 E. Hillsdale Blvd., Suite 100, Foster City, California 94404, United States
    • Martijn Fenaux - Terns Pharmaceuticals, 1065 E. Hillsdale Blvd., Suite 100, Foster City, California 94404, United States
    • Randall L. Halcomb - Terns Pharmaceuticals, 1065 E. Hillsdale Blvd., Suite 100, Foster City, California 94404, United States
  • Author Contributions

    F.A.R. and C.T.J. contributed equally.

  • Notes
    The authors declare the following competing financial interest(s): The authors are employees of and shareholders in Terns Pharmaceuticals.

Biographies

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F. Anthony Romero

F. Anthony Romero is a Director of Chemistry at Terns Pharmaceuticals focusing on drugs to treat liver diseases. Prior to Terns, he was a Director of Chemistry at Unity Biotechnology working on the development of novel senolytic molecules for the treatment of diseases of aging. Before joining Unity, he worked on epigenetic and inhalation programs and helped lead the implementation of fragment-based lead discovery at Genentech. Dr. Romero started his career at Merck focused on fragment-based lead discovery, metabolic disorders, and thrombosis research. He earned his A.B. from Occidental College and Ph.D. from the University of Kansas under Prof. Gary Grunewald. He did a postdoctoral fellowship at The Scripps Research Institute with Prof. Dale Boger.

Christopher T. Jones

Christopher T. Jones is an Associate Director of Biology at Terns Pharmaceuticals focusing on preclinical development of drugs to treat liver diseases including NASH. Prior to Terns, he was a Senior Investigator at Novartis Institutes of BioMedical Research working on early and late stage drug discovery programs that included hepatitis C virus, hepatitis B virus, and innate immunity. He earned his Ph.D. from Purdue University under Dr. Richard Kuhn studying the structural and molecular biology of flaviviruses. His postdoctoral work at the Rockefeller University under Dr. Charles Rice focused on the molecular virology of hepatitis C virus.

Yingzi Xu

Yingzi Xu is a Director of Chemistry at Terns Pharmaceuticals focusing on drugs to treat liver diseases. Prior to Terns, she was a principal scientist at Elan Pharmaceuticals working on multiple sclerosis and Alzheimer’s disease small molecule drug discovery. She earned her Ph.D. from Columbia University under Prof. David Horne and did her postdoctoral research at University of California, Berkeley, with Prof. Henry Rapoport.

Martijn Fenaux

Martijn Fenaux is the Vice President of Biology and Co-Founder of Terns Pharmaceuticals and has 19 years of experience in drug discovery and development of small molecules and vaccines in both academic and industrial settings. He is the co-inventor of the approved livestock vaccine Fostera PCV MH. Dr. Fenaux led and contributed to the discovery and development of multiple antiviral inhibitors at Gilead Sciences and Novartis. Prior to cofounding Terns Pharmaceuticals, he served as a group leader at Novartis Institutes for BioMedical Research where he oversaw the HBV drug discovery program. Prior to Novartis, Dr. Fenaux supported HCV drug discovery efforts at Gilead Sciences. Martijn received his Ph.D. in Virology from Virginia Tech and completed his postdoctoral research at Stanford University.

Randall L. Halcomb

Randall L. Halcomb joined Terns Pharmaceuticals in 2017 as Co-Founder and Senior Vice President, Chemistry and Early Development. Dr. Halcomb was previously at Gilead Sciences as Director, Medicinal Chemistry. In that role, he led programs that delivered multiple clinical candidates and led scientific projects spanning multiple phases of discovery from high throughput screening and lead optimization to early development. More recently Dr. Halcomb held positions at Igenica Biotherapeutics as Vice President, Chemistry, and at Pliant Therapeutics as Vice President, Chemistry, before joining Terns. Earlier in his career, Dr. Halcomb was Associate Professor of Chemistry and Biochemistry at the University of Colorado, Boulder. He received a B.S. from the University of Alabama and Ph.D. from Yale University and completed postdoctoral studies at the Scripps Research Institute.

Acknowledgments

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We thank Catherine Jones for editing assistance and Christine T. Rathbun for figure design assistance.

Abbreviations
ACC

acetyl-CoA carboxylase

ADaM

allosteric drug and metabolite site

ADME

absorption, distribution, metabolism, excretion

ADP

adenosine diphosphate

ALT

alanine transaminase

AMP

adenosine monophosphate

AMPK

5′-adenosine monophosphate-activated protein kinase

AP

alkaline phosphatase

ASBT

apical sodium-dependent bile acid transporter

ASK1

apoptosis signal-regulating kinase 1

AST

aspartate aminotransferase

ATP

adenosine triphosphate

BC

ACC biotin carboxylase domain

CCL2

chemokine ligand 2

CCl4

carbon tetrachloride

CCR

chemokine receptors

CRD

galectin carbohydrate recognition domain

CT

computerized tomography

CTD

ACC carboxyltransferase domain

DGAT

diglyceride O-acyltransferase

DPP-4

dipeptidyl peptidase-4

DPP4i

dipeptidyl peptidase-4 inhibitor

ECG

electrocardiogram

FASN

fatty acid synthase

FGF

fibroblast growth factor

FXR

farnesoid X receptor

Gal-3

galectin 3

GCGR

glucagon receptor

GGT

γ-glutamyl transferase

GIPR

gastric inhibitor polypeptide receptor

GLP-1

glucagon-like peptide-1

GLP-1R

glucagon-like peptide-1 receptor

GPAT

glycerol-3-phosphate acyltransferase

HbA1c

glycated hemoglobin A1c

HCC

hepatocellular carcinoma

HDL

high-density lipoprotein

HER2

human epidermal growth factor receptor 2

hERG

human ether-à-go-go-related gene

HIV

human immunodeficiency virus

HRE

hormone response elements

HVPG

hepatic venous pressure gradient

IBAT

ileal bile acid transporter

IPF

idiopathic fibrosis

JFas

anti-Fas antibody-stimulated Jurkat E6.1 cell lymphoma cell line

JNK

Jun N-terminal kinase

KHK

ketohexokinase

LOX

lysyl oxidase

LOXL2

lysyl oxidase-like 2

LPS

lipopolysaccharide

LTQ

lysine tyrosylquinone

MAG

monoacylglycerol

MAO-A

monoamine oxidase A

MAO-B

monoamine oxidase B

MAP3K

mitogen-activated protein kinase kinase kinase

MELD

model for end-stage liver disease

MPC

mitochondrial pyruvate carrier

MR

mineralocorticoid receptor

MRE

magnetic resonance elastography

MRI-PDFF

magnetic resonance imaging proton density fat fraction

NAFL

nonalcoholic fatty liver

NAFLD

nonalcoholic fatty liver disease

NAS

nonalcoholic fatty liver disease activity score

NASH

nonalcoholic steatohepatitis

NO

nitric oxide

OATP

organic-anion-transporting polypeptide

PBC

primary biliary cholangitis

PK

pharmacokinetics

PPAR

peroxisome proliferator-activated receptor

PSC

primary sclerosing cholangitis

QD

quaque die, one a day

RXR

retinoid X receptor

SAR

structure–activity relationship

SC

subcutaneous

SCD1

stearoyl-coenzyme A desaturase 1

sGC

soluble guanylate cyclase

SGLT

sodium-dependent glucose cotransporter

SHP

small heterodimer partner

SREBP-1c

sterol regulatory element-binding protein 1c

SSAO

semicarbazide-sensitive amine oxidase

STAM

streptozotocin is administered to neonatal mice

sVAP-1

soluble form of VAP-1

T2DM

type 2 diabetes mellitus

TGR5

G protein-coupled bile acid receptor 1

THR-α

thyroid hormone receptor-α

THR-β

thyroid hormone receptor-β

TIMP1

tissue inhibitor of metalloproteinase 1

TNFα

tumor necrosis factor alpha

TRH

thyrotropin releasing hormone

TRX

thioredoxin

TSH

thyroid stimulating hormone

TZD

thiazolidinediones

VAP-1

vascular adhesion protein-1

VLDL

very low density lipoprotein

ZDF

Zucker diabetic fatty

References

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  • Abstract

    Figure 1

    Figure 1. NASH disease is a complex metabolic syndrome that manifests in the liver. Drug targets that are under investigation for NASH and discussed in this review are shown, along with their primary mode(s) of action. It should be noted that some targets are involved in multiple aspects of NASH.

    Figure 2

    Figure 2. PPAR agonists 15. EC50 values for PPAR-α, PPAR-γ, and PPAR-δ are shown.

    Figure 3

    Figure 3. Steroidal FXR agonists, compound 7 and its precursor 6, with reported EC50 values.

    Figure 4

    Figure 4. Nonsteroidal FXR agonists (815) with reported EC50 values. Initial starting points for the optimization of these inhibitors are shown when available.

    Figure 5

    Figure 5. Co-crystal structure of 9 with FXR (PDB 3DCT).

    Figure 6

    Figure 6. (A) Thyroid hormone receptor natural ligands (16 and 17). (B) Overlay of 16 in THR-α (cyan; PDB 2H77) and THR-β (green; PDB 3GWS).

    Figure 7

    Figure 7. THR-β agonist 20 and its precursors 18 and 19. EC50 values for THR-β and THR-α in an in vitro functional assay are shown.

    Figure 8

    Figure 8. THR agonist 23 and its precursors 21 and 22. Receptor binding affinity, Ki values, for THR-β and THR-α are shown.

    Figure 9

    Figure 9. THR agonist prodrugs of 22: 2325.

    Figure 10

    Figure 10. Structures of direct AMPK activators (27, 29, 3133) with reported EC50 values. Initial starting points for the optimization of these inhibitors (when known) are shown (26, 28, 30).

    Figure 11

    Figure 11. Key hydrogen-bonding interactions of the α1β1γ1 isoform of AMPK with 29 (PDB 5KQ5).

    Figure 12

    Figure 12. Structures of ACC inhibitors with their reported IC50 values for ACC isoform inhibition in biochemical assays: (A) 34, (B) 35, (C) 36, (D) co-crystal structure of 36 with ACC (PDB 5KKN), (E) 37, and (F) 38.

    Figure 13

    Figure 13. DGAT inhibitors (3941) with their reported IC50 values for DGAT isoform (when known) inhibition in biochemical assays.

    Figure 14

    Figure 14. FASN inhibitor (42).

    Figure 15

    Figure 15. MPC- and PPAR-γ-targeting compounds (43, 44, and 3). Binding to mitochondrial membranes (indicating MPC1/2 interactions) and activity against PPAR-γ in a biochemical assay are shown.

    Figure 16

    Figure 16. IBAT inhibitors (4547) with their reported IC50 values.

    Figure 17

    Figure 17. Structures of KHK inhibitors (50 and 51) with their reported IC50 values. Examples of starting fragments for the optimization of these inhibitors (48 and 49) are also shown.

    Figure 18

    Figure 18. Co-crystal structure of 50 with human KHK [PDB 5WBZ].

    Figure 19

    Figure 19. Structures of peptide GLP-1R agonists (5254).

    Figure 20

    Figure 20. Structures of GLP-1R agonists (55, 56, and 58) with their reported EC50 values. An example of an optimization starting point is also shown (57).

    Figure 21

    Figure 21. Structures of SGLT inhibitors (59, 61, 6365, 67) with their reported IC50 or EC50 values against SGLT1 and SGLT2 in vitro. Initial starting points (60, 62, 66) for the optimization of these inhibitors are also shown.

    Figure 22

    Figure 22. SCD1 inhibitor (68).

    Figure 23

    Figure 23. Evolution of ASK1 inhibitor 72 with reported IC50 and EC50 values.

    Figure 24

    Figure 24. Crystal structures of compounds (A) 69, (B) 70, and (C) 71 with ASK1 (PDB 6E2M, 6E2N, and 6E2O, respectively).

    Figure 25

    Figure 25. Caspase inhibitor 74 and precursor 73.

    Figure 26

    Figure 26. CCR2/5 antagonist 76 and its precursor 75. IC50 values for CCR2 and CCR5 binding are shown.

    Figure 27

    Figure 27. MR antagonists (77 and 78)

    Figure 28

    Figure 28. VAP-1 inhibitors (7982) and their reported IC50 values for VAP-1, MAO-A, and MAO-B.

    Figure 29

    Figure 29. LOXL2 inhibitors (83, 84, and 86) with reported IC50 values in cell culture media (CCM) and whole blood (hWB) and LOX IC50 values.

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